Somatostatin antagonists and agonists that act at the SST subtype 2 receptor

ABSTRACT

Compounds according formula (I)  
     A—G—Z—W  
     and pharmaceutically acceptable salts, solvates or hydrates thereof; wherein,  
     A is (C 6 -C 10 )aryl, (C 6 -C 10 )aryl-SO 2 , (C 6 -C 10 )aryl-CH 2 —, (C 6 -C 10 )arylcarbonyl, (C 1 -C 9 )heteroaryl, (C 1 -C 9 )heteroaryl-SO 2 —, (C 1 -C 9 )heteroaryl-CH 2 —; or (C 1 -C 9 )heteroarylcarbonyl;  
     G is selected from the group consisting of:  
                 
 
     where B is (C 6 -C 10 )aryl or (C 1 -C 9 )heteroaryl, and X is CH 2 , SO 2 , or carbonyl;  
                 
 
     where X is CH 2 , SO 2 , or carbonyl; and R 1  and R 1′  are each independently selected from H, CN, (C 1 -C 8 )alkyl-, and phenyl(CH 2 )—, wherein said alkyl and phenyl groups are optionally substituted; and  
                 
 
     where Z and W are as defined in the present Specificiation; and pharmaceutical compositions and methods useful to increase secretion of growth hormone(GH) from the anterior pituitary of mammals, including on a sustained release basis.

FIELD OF THE INVENTION

[0001] The present invention provides pharmaceutically active compoundsthat facilitate secretion of growth hormone (GH) by the anteriorpituitary. Growth hormone (also known as somatotropin) acts indirectlyto promote skeletal growth in children by stimulating the production ofinsulin like growth factor-1 from the liver. Growth hormone alsostimulates the differentiation of fat cells and chondrocytes (cells thatsecrete collagen and proteoglycans to form cartilage). In adults, growthhormone is involved in the proper maintenance of connective and muscletissues.

[0002] Growth hormone deficiency may be congenital or acquired.Deficiency in children causes slow skeletal growth that, if notcorrected, results in permanent short stature. In older adults,deficiency of growth hormone results in frailty. Additional adultsymptoms of GH deficiency may include wrinkled skin and hypoglycemia.

[0003] For veterinary application, upregulation of growth hormone isuseful to treat frailty in older animals, particularly companionanimals. With respect to livestock, upregulation of growth hormoneincreases growth and performance, even in healthy animals with normal GHlevels. Improvements in feed efficiency milk yield, leanness, meatquality and fertility are of note.

[0004] Although direct administration of growth hormone may be effectivein certain therapeutic applications, it is difficult in practice. Amongother issues, since the half-life of growth hormone in the body is veryshort, direct administration leads to artificially increased levels inthe concentration of circulating GH, which then rapidly drop off.Sustained release, such as by a mechanical pump, has not been optimallyset to practice.

[0005] The concentration of growth hormone circulating in the bodydepends on the balance of numerous biochemical pathways, includingopposing processes. Compared to the direct administration approach,shifting the balance of these pathways indirectly provides a safer, morereproducible method to affect GH secretion on a sustained basis. Underthis approach, since the overall regulatory framework remains intact,secretion rates and circulatory concentrations for GH follow arelatively normal pattern, and adverse fluctuations in both secretionrate and circulating GH concentration are avoided. The present inventionprovides for therapeutic compounds, and their use, to indirectly elevategrowth hormone secretion from the pituitary.

Reported Developments

[0006] Growth hormone is released from the anterior pituitary inresponse to stimulation by growth hormone releasing peptide (GHRP), andgrowth hormone releasing hormone (GHRH), of hypothalmic origin. However,release of growth hormone via these or other mechanisms is inhibited bysomatostatin, and thus the process is closely regulated.

[0007] Somatostatin (SRIF) is a cyclic peptide hormone of 14 amino acids(there is also a 28 amino acid form) having numerous endocrine functionswhich, like many hormones, is cleaved from a larger precursor protein.Somatostatin inhibits the pituitary secretion of growth hormone, thepancreatic secretion of glucagon and insulin, and the secretion ofgastrin from the gut. Somatostatin also acts as aneurotransmitter/neuromodulator (see S. J. Hocart et al., J. Med.Chem.,41, pp. 1146-1154, 1998 for a general discussion).

[0008] The biological effects of somatostatin are apparently allinhibitory in nature, and are elicited upon binding to the surface of atarget cell. The receptor is an integral membrane protein (which spansthe cell membrane), and is G-protein-coupled. G-protein coupledreceptors represent a major class of cell surface receptors. It isbelieved that upon binding of somatostatin to the receptor, the receptorundergoes a conformational change facilitating its interaction with aG-protein at the cytoplasmic face of the receptor. This facilitatesbinding or release of GTP/GDP at the G protein, and leads to furtheractivation and signaling events inside the cell. In particular,somatostatin binding at its own G-protein-coupled receptor is negativelycoupled to adenylyl cyclase activity, which is necessary for theproduction of cyclic AMP. Thus, these further signaling events directlyoppose mechanisms (for example, as mediated by calcium ions or cyclicAMP) whereby GHRP and GHRH would otherwise trigger extracellularsecretion of growth hormone from cytoplasmic storage granules. For ageneral review thereof, see The Encyclopedia of Molecular Biology, J.Kendrew, ed., Blackwell Science, Ltd. 1994, at page 387.

[0009] The effects of somatostatin on target cells are mediated by atleast 5 classes of receptors (sst1-sst5). Although the receptors mayhave similar affinity for somatostatin, they are differentiallyexpressed in different tissues, and so positioned, interact, directly orindirectly, with different intracellular signaling components. Thistissue specificity of receptor expression accounts in large measure forthe different effects of somatostatin in different target cell types.Somatostatin receptors are found, for example, in tissues of theanterior pituitary, other brain tissues, the pancreas, the lung, onlymphocytes, and on mucosa cells of the intestinal tract.

[0010] The sst2 type receptor is known to mediate inhibition of growthhormone secretion in the anterior pituitary. This receptor is alsoreported in 2 forms, proteins sst2A and sst2B, which result fromdifferential splicing of the sst2 gene transcript (M. Vanetti, et al.,FEBS Letters, 311, pp.290-294, 1992). The sst2 receptor is also known tomediate inhibition of gastrin and histamine secretion. Additionally, thesst2 receptor is known to mediate inhibition of glucagon release frompancreatic alpha cells.

[0011] Although numerous somatostatin agonists have been described (seefor example, WO 98/44922, WO 98/45285, and WO 98/44921), the developmentof useful sst2-linked somatostatin antagonists has lagged behind. Recentreports of such compounds include W. R. Baumbach et al., MolecularPharmacology, 54, pp. 864-873, 1998, and S. J. Hocart et al., J. Med.Chem., 41, pp. 1146-1154, 1998.However, such compounds are shortpeptides, a class of molecules not often suited for successful use aspharmaceuticals because of their typically short half life in the body.

[0012] It would be advantageous to provide antagonists of somatostatinactivity, effective at the sst2 type receptor, having superiorproperties as pharmaceuticals, including bioavailability, stability, andthe like. The present invention provides a series of antagonistcompounds that specifically interfere with the binding of somatostatinto the sst subtype 2 receptors of cells in the mammalian anteriorpituitary, and which have additional valuable properties.

SUMMARY OF THE INVENTION

[0013] According to the practice of the present invention, there isprovided a compound according to formula (I)

A—G—Z—W  (I)

[0014] or a pharmaceutically acceptable salt, solvates or hydratethereof,

[0015] wherein group A is (C₆-C₁₀)aryl, (C₆-C₁₀)aryl-SO₂,(C₆-C₁₀)aryl-CH₂—, (C₆-C₁₀)arylcarbonyl, (C₁-C₉)heteroaryl,(C₁-C₉)heteroaryl-SO₂—, (C₁-C₉)heteroaryl-CH₂—; or(C₁-C₉)heteroarylcarbonyl;

[0016] G is:

[0017] where B is (C₆-C₁₀)aryl or (C₁-C₉)heteroaryl, and X is CH₂, SO₂,or carbonyl;

[0018] where X is CH₂, SO₂, or carbonyl; and R¹ and R^(1′) are eachindependently selected from H, CN, (C₁-C₈)alkyl-, and phenyl(CH₂)—,wherein said alkyl and phenyl groups are optionally substituted; or

[0019] wherein R² is H, (C₁-C₈)alkyl, or is selected from groups Aabove; and E is selected from groups A above;

[0020] W is (a):

[0021] wherein n is 2 to 5,

[0022] R is selected from H, (C₁-C₈)alkyl-, and phenyl(CH₂)—, whereinsaid alkyl and phenyl groups are optionally substituted;

[0023] R⁶ is selected from H, (C₁-C₈)alkyl-, and phenyl(CH₂)—, whereinsaid alkyl and phenyl groups are optionally substituted;

[0024] R⁴ is selected from H, (C₁-C₈)alkyl-, and phenyl(CH₂)—, whereinsaid alkyl and phenyl groups are optionally substituted; or is

[0025] where groups R¹⁰, R¹¹ and R¹² are each, independently, selectedfrom H, (C₁-C₈)alkyl-, and phenyl(CH₂)—, and R¹⁰ may also be selectedfrom (C₆-C₁₀)aryl, wherein said alkyl, phenyl or other aryl groups areoptionally substituted;

[0026] R⁵ is H, (C₁-C₈)alkyl-, and phenyl(CH₂)—, wherein said alkyl andphenyl groups are optionally substituted, or is

[0027] wherein R¹² and R¹² are each independently selected from H,(C₁-C₈)alkyl-, and phenyl(CH₂)—, wherein said alkyl and phenyl groupsare optionally substituted; or

[0028] W is (b)

[0029] wherein

[0030] Q is selected from the group consisting of (C₆-C₁₀)aryl,(C₁-C₉)heteroaryl, (C₃-C₁₀)cycloalkyl, and (C₃-C₁₀)heterocycloalkyl; and

[0031] R⁷, R⁸, and R⁹ are each independently selected from H,(C₁-C₈)alkyl-, and phenyl(CH₂)—, wherein said alkyl and phenyl groupsare optionally substituted.

[0032] In a preferred aspect of the invention, there is provided acompound wherein, independently, one or more of groups A, B, E, and Qtherein comprise, a (C₆-C₁₀)aryl group, selected from phenyl andnaphthyl.

[0033] In a preferred aspect of the invention, there is provided acompound wherein, independently, one or more of groups A, B, E, and Qtherein comprise, a (C₁-C₉)heteroaryl group, selected from furyl,thienyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl,pyrrolyl, triazolyl, tetrazolyl, imidazolyl, 1,3,5-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,3-oxadiazolyl, 1,3,5-thiadiazolyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, pyridyl, pyrimidyl, pyrazinyl,pyridazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl,pyrazolo[3,4-b]pyridinyl, cinnolinyl, pteridinyl, purinyl,6,7-dihydro-5H-[1]pyrindinyl, benzo[b]thiophenyl, 5, 6, 7,8-tetrahydro-quinolin-3-yl, benzoxazolyl, benzothiazolyl,benzisothiazolyl, benzisoxazolyl, benzimidazolyl, thianaphthenyl,isothianaphthenyl, benzofuranyl, isobenzofuranyl, isoindolyl, indolyl,indolizinyl, indazolyl, isoquinolyl, quinolyl, phthalazinyl,quinoxalinyl, quinazolinyl, and benzoxazinyl.

[0034] In a preferred aspect of the invention, there is provided acompound wherein group Q therein is selected from

[0035] (a) a (C₆-C₁₀)aryl group, selected from phenyl and naphthyl;

[0036] (b) a (C₁-C₉)heteroaryl group, selected from furyl, thienyl,thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl,triazolyl, tetrazolyl, imidazolyl, 1,3,5-oxadiazolyl, 1,2,4-oxadiazolyl,1,2,3-oxadiazolyl, 1,3,5-thiadiazolyl, 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl,1,2,4-triazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl,pyrazolo[3,4-b]pyridinyl, cinnolinyl, pteridinyl, purinyl,6,7-dihydro-5H-[1]pyrindinyl, benzo[b]thiophenyl, 5, 6, 7,8-tetrahydro-quinolin-3-yl, benzoxazolyl, benzothiazolyl,benzisothiazolyl, benzisoxazolyl, benzimidazolyl, thianaphthenyl,isothianaphthenyl, benzofuranyl, isobenzofuranyl, isoindolyl, indolyl,indolizinyl, indazolyl, isoquinolyl, quinolyl, phthalazinyl,quinoxalinyl, quinazolinyl, and benzoxazinyl;

[0037] (c) a (C₃-C₁₀)cycloalkyl group, selected from cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopropenyl,cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl,1,3-cyclobutadienyl, 1,3-cyclopentadienyl, 1,3-cyclohexadienyl,1,4-cyclohexadienyl, 1,3-cycloheptadienyl, 1,4-cycloheptadienyl,1,3,5-cycloheptatrienyl, bicyclo[3.2.1]octane, bicyclo [2.2.1] heptaneand the norborn-2-ene unsaturated form thereof; and

[0038] (d) a (C₃-C₁₀)heterocycloalkyl group, selected from pyrrolidinyl,tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, pyranyl,thiopyranyl, aziridinyl, oxiranyl, methylenedioxyl, chromenyl,isoxazolidinyl, 1,3-oxazolidin-3-yl, isothiazolidinyl,1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl, 1,3-pyrazolidin-1-yl,piperidinyl, thiomorpholinyl, 1,2-tetrahydrothiazin-2-yl,1,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazinyl, morpholinyl,1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl,tetrahydroazepinyl, piperazinyl, and chromanyl.

[0039] In a highly preferred embodiment of the invention, there isprovided a compound wherein the Z group thereof has thestereospecificity

[0040] In further examples of this embodiment, the Z group defines anL-amino acid selected from the group consisting of L-tryptophanyl-,L-histidinyl-, L-3-methylhistidinyl-, L-phenylalaninyl-,L-diphenylalaninyl-, L-3-fluorophenylalaninyl-,L-2-fluorophenylalaninyl-, L-4-fluorophenylalaninyl-, and L-tyrosinyl-,and is most preferably L-tryptophanyl-.

[0041] In a further preferred embodiment of the invention, there isprovided a compound wherein the Z group thereof has thestereospecificity

[0042] and thus the Z group defines an D-amino acid which is preferablyD-tryptophanyl.

[0043] In a further highly preferred embodiment of the invention, thereis provided a compound wherein the W group thereof has an absolutestereospecific configuration at the indicated position which correspondsto the that of the α-carbon of L-amino acids.

[0044] It is further preferred that the W group define an L-lysine groupor a (C₁-C₈)alkyl ester thereof, or an L-arginine group or a(C₁-C₈)alkyl ester thereof, most preferably an (C₁-C₈)alkyl ester ofL-lysine. Additionally, the W group can define an L-diaminopimelic,L-canavanine, L-ornithine, L-2,4-diaminobutyric, L-5-hydroxylysine,L-epsilon-N-methyllysine, L-histidine, or L-3-methylhistidine group.

[0045] Accordingly, preferred compounds of the invention include:

[0046]6-Amino-2-[2-[(biphenyl-4-ylmethyl)-amino]-3-(1H-indol-3-yl)-propionylamino]-hexanoicacid methyl ester;

[0047]2-{3-(3-Fluoro-phenyl)-2-[2-(toluene-4-sulfonylamino)-acetylamino]-propionylamino}-5-guanidino-pentanoicacid methyl ester;

[0048]6-Amino-2-[2-[(biphenyl-4-carbonyl)-amino]-3-(1H-indol-3-yl)-propionylamino]-hexanoicacid methyl ester;

[0049]2-{2-[(Biphenyl-4-carbonyl)-amino]-3,3-diphenyl-propionylamino}-5-guanidino-pentanoicacid methyl ester;

[0050]6-Amino-2-[2-[(biphenyl-4-carbonyl)-amino]-3-(1H-indol-3-yl)-propionylamino]-hexanoicacid tert-butyl ester;

[0051]6-Amino-2-[2-(2-benzenesulfonylamino-2-methyl-propionylamino)-3-(1H-indol-3-yl)-propionylamino]-hexanoicacid tert-butyl ester; and6-Amino-2-[2-[(biphenyl-4-carbonyl)-amino]-3-(1H-indol-3-yl)-propionylamino]-hexanoicacid tert-butyl ester.

[0052] Additional compounds of the invention include:

[0053]2-{3-(3-Fluoro-phenyl)-2-[2-(toluene-4-sulfonylamino)-acetylamino]-propionylaminol}-5-guanidino-pentanoicacid tert-butyl ester;

[0054]2-{3-(4-Fluoro-phenyl)-2-[2-(toluene-4-sulfonylamino)-acetylamino]-propionylaminol}-5-guanidino-pentanoicacid methyl ester;

[0055]2-{3-(3-Fluoro-phenyl)-2-[2-(toluene-4-sulfonylamino)-2-methylpropionylamino]-propionylamino}-5-guanidino-pentanoicacid methyl ester;

[0056]6-Amino-2-[2-[(biphenyl-4-carbonyl)-amino]-3-(1H-indol-3-yl)-propionylamino]-hexanoicacid tert-butyl ester;

[0057]6-Amino-2-[2-[(biphenyl-4-carbonyl)-amino]-2-methyl-3-(1H-indol-3-yl)-propionylamino]-hexanoicacid tert-butyl ester;

[0058]N-(3-aminomethyl-cyclohexylmethyl)-3-(1H-indol-3-yl)-2-(2-benzenesulfonylamino-2-methyl-propionylamino)-propionamide;and

[0059]N-(4-aminomethyl-pyrid-2-ylmethyl)-3-(1H-indol-3-yl)-2-[(biphenyl-4-carbonyl)-amino]-propionamide.

[0060] In further compounds of the invention, R¹ or R^(1′) is(C₁-C₈)alkyl- or phenyl(CH₂)— and said alkyl or phenyl group isoptionally substituted by one or more halo or trifluoro(C₁-C₈)alkylgroups.

[0061] In further compounds of the invention, R² is (C₁-C₈)alkyl-,optionally substituted by one or more halo or trifluoroalkyl groups,most preferably (C₁-C₃)alkyl-, optionally substituted by one or morehalo or trifluoro(C₁-C₈)alkyl groups.

[0062] In further compounds of the invention, one or more of R³, R⁴, R⁵,and R⁶ is (C₁-C₈)alkyl- or phenyl(CH₂)—, and said alkyl or phenyl groupis optionally substituted by one or more halo or trifluoro(C₁-C₈)alkylgroups.

[0063] In further compounds of the invention, one or more of R⁷, R⁸, andR⁹ is (C₁-C₈)alkyl- or phenyl(CH₂)—, and said alkyl or phenyl group isoptionally substituted by one or more halo or trifluoro(C₁-C₈)alkylgroups.

[0064] In further compounds of the invention, one or more of R¹⁰, R¹¹,R^(11′), R¹² and R¹² is (C₁-C₈)alkyl- or phenyl(CH₂)—, and said alkyl orphenyl group is optionally substituted by one or more halo ortrifluoro(C₁-C₈)alkyl groups.

[0065] With respect to trifluoro(C₁-C₈)alkyl substituent groups, all asaforementioned, the prefered group is trifluoromethyl.

[0066] The compound of formula (I) may have chiral centers and thereforeexist in different enantiomeric forms. This invention relates to alloptical isomers, tautomers and stereoisomers of the compounds of formula(I), and mixtures thereof, although as will be described below ingreater detail, certain isomeric structures are preferred.

[0067] The present invention also relates to the pharmaceuticallyacceptable acid addition salts of compounds of the formula (I). Theacids which are used to prepare the pharmaceutically acceptable acidaddition salts of the aforementioned base compounds of this inventionare those which form non-toxic acid addition salts, i.e., saltscontaining pharmacologically acceptable anions, such as thehydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate,phosphate, acid phosphate, acetate, lactate, citrate, acid citrate,tartrate, bitartrate, succinate, maleate, fumarate, gluconate,saccharate, benzoate, methanesulfonate, ethanesulfonate,benzenesulfonate, p-toluenesulfonate and pamoate [i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)]salts.

[0068] With respect to the relatively limited number of compounds thatso permit, the invention also relates to base addition salts of formula(I). The chemical bases that may be used as reagents to preparepharmaceutically acceptable base salts of those compounds of formula Ithat are acidic in nature are those that form non-toxic base salts withsuch compounds. Such non-toxic base salts include, but are not limitedto those derived from such pharmacologically acceptable cations such asalkali metal cations (e.g., potassium and sodium) and alkaline earthmetal cations (e.g, calcium and magnesium), ammonium or water-solubleamine addition salts such as N-methylglucamine-(meglumine), and thelower alkanolammonium and other base salts of pharmaceuticallyacceptable organic amines.

[0069] The subject invention also includes isotopically-labelledcompounds, which are identical to those recited in Formula (I), but forthe fact that one or more atoms are replaced by an atom having an atomicmass or mass number different from the atomic mass or mass numberusually found in nature. Examples of isotopes that can be incorporatedinto compounds of the invention include isotopes of hydrogen, carbon,nitrogen, oxygen, phosphorous, fluorine and chlorine, such as ²H, ³H,¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively.Compounds of the present invention, prodrugs thereof, andpharmaceutically acceptable salts of said compounds or of said prodrugswhich contain the aforementioned isotopes and/or other isotopes of otheratoms are within the scope of this invention. Certainisotopically-labelled compounds of the present invention, for examplethose into which radioactive isotopes such as ³H and ¹⁴C areincorporated, are useful in drug and/or substrate tissue distributionassays. Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C, isotopes areparticularly preferred for their ease of preparation and detectability.Further, substitution with heavier isotopes such as deuterium, i.e., ²H,can afford certain therapeutic advantages resulting from greatermetabolic stability, for example increased in vivo half-life or reduceddosage requirements and, hence, may be preferred in some circumstances.Isotopically labelled compounds of Formula (I) of this invention andprodrugs thereof can generally be prepared by carrying out theprocedures disclosed in the Schemes and/or in the Examples andPreparations below, by substituting a readily available isotopicallylabelled reagent for a non-isotopically labelled reagent.

[0070] The present invention also relates to a pharmaceuticalcomposition for increasing growth hormone secretion in a mammal,including a human, comprising an effective amount of a compoundaccording to formula 1, and a pharmaceutical carrier. The presentinvention also relates to a pharmaceutical composition for increasinggastrin secretion or glucagon secretion in a mammal, comprising aneffective amount of a compound according to formula 1, and apharmaceutical carrier.

[0071] The present invention also relates to a pharmaceuticalcomposition for the treatment of diseases characterized by decreasedlevels of growth hormone, glucagon, or gastrin in a mammal, including ahuman, comprising an amount of a compound of formula (I) effective insuch treatments and a pharmaceutically acceptable carrier. The presentinvention also relates to a pharmaceutical composition for the treatmentof diseases in a mammal, including a human, wherein treatment can beeffected by inhibiting the binding of somatostatin to the sst2-typereceptor therefor, comprising an effective amount of a compoundaccording to formula 1, and a pharmaceutical carrier.

[0072] The present invention relates to a method for treating growthhormone deficiency in a mammal, including a human. The present inventionalso relates to elevating the level of growth hormone in a mammal,including a human, wherein this is beneficial to the mammalnothwithstanding that the natural levels of growth hormone present inthe mammal are within the normal range. In the practice of said method,there is administered a phamaceutical composition of the inventioncomprising a compound according to formula (1), and a pharmceuticalcarrier.

[0073] Similarly, the methods of the invention provide for increasinggastrin secretion or glucagon secretion in a mammmal, including a human,where this is medically appropriate. For example, gastrin is involved inprotection of gastric mucosa against damage by chemical substances, e.g.alcohol (S. J. Konturek et al., European Journal of Pharmacology,278(3), pp. 203-212, 1995). Glucagon is a counter-regulatory hormonethat is used to treat hypoglycemia, and causes positive inotropic andchronotropic effects without the need for beta-1 adrenoceptorstimulation. It also can be used to correct beta-blocker, verapamil andimipramine overdose, and is used as adjunctive therapy in shocksituations, for heart failure, and in treating postcountershock asystole(see C. M. White, Journal of Clinical Pharmacology,. 39(5), pp. 442-447,1999)

[0074] In preferred examples of the invention, there are providedmethods for treating a human for one or more symptoms of insufficientgrowth hormone secretion, or one or more conditions that may occurtherewith and be exacerbated thereby, wherein said condition is selectedfrom frailty, hypoglycemia, wrinkled skin, slow skeletal growth, reducedimmune function, reduced organ functon, fertility disorders, bonedisease, AIDS-related complex, cachexia, cardiac failure, ischemic heartdisease, colon disease, metabolic disorders, renal failure, musculardystrophy, and Turners syndrome, comprising administering an effectiveamount of a pharmaceutical composition as aforementioned.

[0075] In a further preferred example of the invention, there isprovided a method for treating a non-human mammal to enhance the growthand performance thereof, comprising administering an effective amount ofa pharmaceutical composition as aforementioned. Enhancement of growthand performance includes, for example, increased feed efficiency,improved milk yield or fertility, and increased leanness.

[0076] A highly preferred example of the invention provides a methodwhereinby secretion of growth hormone, gastrin, or glucagon can beincreased on a sustained basis in a mammal, including a human, in needthereof, comprising adminstering a dose of a pharmaceutical compositionas aforementioned. According to this example of the invention,physiologically adverse consequences of artificial fluctuations in thecirculating (or locally needed) concentrations of these hormones can beavoided.

[0077] Although the pharmaceutical compositions and methods of theinvention are described primarily in terms of use with humans, andnon-human mammals, the skilled practitioner will immediately appreciatethat the invention, in many of its aspects, may be usefully practicedwith respect to birds, such as chickens and turkeys, and also fishes.

[0078] Definitions

[0079] In connection with the practice of the invention, the followingdefinitions will generally apply.

[0080] The term “treating”, as used herein, refers to reversing,alleviating, inhibiting the progress of, or preventing the disorder orcondition to which such term applies, or one or more symptoms of suchdisorder or condition. The term “treatment”, as used herein, refers tothe act of treating, as “treating” is defined immediately above.

[0081] The term “alkyl”, as used herein, unless otherwise indicated,includes saturated monovalent hydrocarbon radicals having straight,branched or cyclic moieties or combinations thereof. Similarly, theterms “alkenyl” and “alknyl” define hydrocarbon radicals havingstraight, branched or cyclic moities wherein at least one double bond,or at least one triple bond, respectively, is present. Such definitionsalso apply when the alkyl, alkenyl or alkynyl group is present withinanother group, such as alkoxy or alkylamine.

[0082] The term “alkoxy”, as used herein, includes O-alkyl groupswherein “alkyl” is as defined above.

[0083] The term “halo”, as used herein, unless otherwise indicated,includes fluoro, chloro, bromo or iodo.

[0084] An “aryl” group as used herein, unless otherwise indicated,includes an organic radical derived from a monocyclic or bicylic(C₆₋C₁₀) aromatic hydrocarbon compound by removal of a hydrogen radicalfrom a ring carbon of the aryl compound. An aryl group is optionallysubstituted by one or more substituents wherein, unless otherwiseindicated, selection of each optional substituent is independent ofselection of any other optional substituents, and perferably the numberof optional substituents is between 0 and 3, more preferably between 0and 2. It will be appreciated that the preferred number of substituentsis determined in part by facility of synthesis. Representative arylgroups are phenyl and naphthyl.

[0085] A “heteroaryl” group as used herein, unless otherwise indicated,includes an organic radical derived from a monocyclic or bicyclic(C₁₋C₉) aromatic heterocyclic compound by removal of a hydrogen radicalfrom a ring atom of the heteroaryl compound, said ring atom beinguncharged in said compound. A heteroaryl group is optionally substitutedby one or more substituents wherein, unless otherwise indicated,selection of each optional substituent is independent of selection ofany other optional substituents, and perferably the number of optionalsubstituents is between 0 and 3, more preferably between 0 and 2. Itwill be appreciated that the preferred number of substituents isdetermined in part by facility of synthesis. Representative heteroarylgroups include furyl, thienyl, thiazolyl, pyrazolyl, isothiazolyl,oxazolyl, isoxazolyl, pyrrolyl, triazolyi, tetrazolyl, imidazolyl,1,3,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-oxadiazolyl,1,3,5-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, pyridyl,pyrimidyl, pyrazinyl, pyridazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl,1,3,5-triazinyl, pyrazolo[3,4-b]pyridinyl, cinnolinyl, pteridinyl,purinyl, 6,7-dihydro-5H-[1]pyrindinyl, benzo[b]thiophenyl, 5, 6, 7,8-tetrahydro-quinolin-3-yl, benzoxazolyl, benzothiazolyl,benzisothiazolyl, benzisoxazolyl, benzimidazolyl, thianaphthenyl,isothianaphthenyl, benzofuranyl, isobenzofuranyl, isoindolyl, indolyl,indolizinyl, indazolyl, isoquinolyl, quinolyl, phthalazinyl,quinoxalinyl, quinazolinyl, and benzoxazinyl; and the like.

[0086] A “cycloalkyl” group as used herein, unless otherwise indicated,includes an organic i=radical derived from a monocyclic(C₃-C₁₀)cycloalkyl compound, by removal of a hydrogen radical from aring carbon of the cycloalkyl compound. A cycloalkyl group is optionallysubstituted by one or more substituents wherein, unless otherwiseindicated, selection of each optional substituent is independent ofselection of any other optional substituents, and perlerably the numberof optional substituents is between 0 and 3, more preferably between 0and 2. It will be appreciated that the preferred number of substituentsis determined in part by facility of synthesis. Representativecycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclopropenyl, cyclobutenyl, cyclopentenyl,cyclohexenyl, cycloheptenyl, 1,3-cyclobutadienyl, 1,3-cyclopentadienyl,1,3-cyclohexadienyl, 1,4-cyclohexadienyl, 1,3-cycloheptadienyl,1,4-cycloheptadienyl, 1,3,5-cycloheptatrienyl, bicyclo[3.2.1]octane,bicyclo [2.2.1] heptane, and the norborn-2-ene unsaturated form thereof.

[0087] A “heterocycloalkyl” group as used herein, unless otherwiseindicated, includes an organic radical derived from a monocyclic(C₃-C₁₀)heterocycloalkyl compound by removal of a hydrogen radical froma ring atom of the heterocycloalkyl compound, said ring atom beinguncharged in said compound. (fix) A heterocycloalkyl group is optionallysubstituted by one or more substituents wherein, unless otherwiseindicated, selection of each optional substituent is independent ofselection of any other optional substituents, and perferably the numberof optional substituents is between 0 and 3, more preferably between 0and 2. It will be appreciated that the preferred number of substituentsis determined in part by facility of synthesis. Representativeheterocycloalkyl groups include pyrrolidinyl, tetrahydrofuranyl,dihydrofuranyl, tetrahydropyranyl, pyranyl, thiopyranyl, aziridinyl,oxiranyl, methylenedioxyl, chromenyl, isoxazolidinyl,1,3-oxazolidin-3-yl, isothiazolidinyl, 1,3-thiazolidin-3-yl,1,2-pyrazolidin-2-yl, 1,3-pyrazolidin-1-yl, piperidinyl,thiomorpholinyl, 1,2-tetrahydrothiazin-2-yl, 1,3-tetrahydrothiazin-3-yl,tetrahydrothiadiazinyl, morpholinyl, 1,2-tetrahydrodiazin-2-yl,1,3-tetrahydrodiazin-1-yl, tetrahydroazepinyl, piperazinyl, andchromanyl.

[0088] In connection with the terms “aryl” group, “heteroaryl” group,“cycloalkyl” group and “heterocycloalkyl” group, as herein defined, theterm “optionally substituted” means that one or more chemically andpharmaceutically acceptable functional groups may be bonded thereto.Such a group contributes properties useful to production, storage, oruse of the inventive compounds as pharmaceuticals, or at least does notsubstantially negate their pharmacological activity. Such suitablesubstituents may be determined by those skilled in the art. Illustrativeexamples of suitable substituents include, but are not limited to,hydroxy, halo, amino, trifluoromethyl, carboxy, (C₁-C₆)alkoxy-,(C₁-C₆)acyloxy-, (C₁-C₆)alkylamino-, ((C₁-C₆)alkyl)₂amino-,(C₁-C₆)acylamino-, cyano, nitro, (C₁-C₆)alkyl-, (C₂-C₆)alkenyl-,(C₂-C₆)alkynyl-, (C₁-C₆)acylamino-, cyano(C₁-C₆)alkyl-,trifluoromethyl(C₁-C₆)alkyl-, nitro(C₁-C₆)alkyl-,(C₁-C₃)alkyl(difluoromethylene)(C₁-C₃)alkyl-,(C₁-C₆)acylamino(C₁-C₆)alkyl-, (C₁-C₆)alkoxy(C₁-C₆)acylamino-,amino(C₁-C₆)acyl-, amino(C₁-C₆)acyl(C₁-C₆)alkyl-,(C₁-C₆)alkylamino(C₁-C₆)acyl-, ((C₁-C₆)alkyl)₂amino(C₁-C₆)acyl-,(C₃-C₁₀)cycloalkyl(C₁-C₆)alkyl-, (C₁-C₆)acyloxy(C₁-C₆)alkyl-,(C₂-C₆)alkoxy(C₁-C₆)alkyl-, piperazinyl(C₁-C₆)alkyl-,(C₁-C₆)acylamino(C₁-C₆)alkyl-, (C₆-C₁₀)aryl(C₁-C₆)alkoxy(C₁-C₆)alkyl-,(C₂-C₉)heteroaryl(C₁-C₆)alkoxy(C₁-C₆)alkyl-,(C₁-C₆)alkylthio(C₁-C₆)alkyl-, (C₆-C₁₀)arylthio(C₁-C₆)alkyl-,(C₁-C₆)alkylsulfinyl(C₁-C₆)alkyl- (C₆-C₁₀)arylsulfinyl(C₁-C₆)alkyl-,(C₁-C₆)alkylsulfonyl(C₁-C₆)alkyl-, (C₆-C₁₀)arylsulfonyl(C₁-C₆)alkyl-,amino(C₁-C₆)alkyl-, (C₁-C₆)alkylamino(C₁-C₆)alkyl-,(C₁-C₆)alkyl(difluoromethylene)-,(C₁-C₃)alkyl(difluoromethylene)(C₁-C₃)alkyl-, (C₁-C₆)alkoxy(C₁-C₆)acyl-,(C₁-C₆)alkylamino(C₁-C₆)acyl-, ((C₁-C₆)alkyl)₂amino(C₁-C₆)acyl-,(C₆-C₁₀)aryl-, (C₅-C₉)heteroaryl-, (C₆-C₁₀)aryl(C₁-C₆)alkyl-,(C₂-C₉)heteroayl(C₁-C₆)alkyl-, (C₆-C₁₀)aryl(C₆-C₁₀)aryl-,(C₆-C₁₀)aryl(C₆-C₁₀)aryl(C₁-C₆)alkyl- (C₃-C₁₀)cycloalkyl-,(C₃-C₆)cycloalkyl(C₁-C₆)alkyl-, (C₃-C₁₀)heterocycloalkyl-,(C₃-C₁₀)heterocycloalkyl(C₁-C₆)alkyl-, hydroxy(C₂-C₆)alkyl-,(C₁-C₆)acyloxy(C₂-C₆)alkyl-, (C₁-C₆)alkoxy(C₂-C₆)alkyl-,piperazinyl(C₁-C₆)alkyl-, (C₁-C₆)acylamino(C₁-C₆)alkyl-,(C₆-C₁₀)aryl(C₁-C₆)alkoxy(C₁-C₆)alkyl-,(C₂-C₉)heteroaryl(C₁-C₆)alkoxy(C₁-C₆)alkyl-,(C₁-C₆)alkylthio(C₁-C₆)alkyl-, (C₆-C₁₀)arylthio(C₁-C₆)alkyl-,(C₁-C₆)alkylsulfinyl(C₁-C₆)alkyl-, (C₆-C₁₀)arylsulfinyl(C₁-C₆)alkyl-,(C₁-C₆)alkylsulfonyl(C₁-C₆)alkyl-, (C₆-C₁₀)arylsulfonyl(C₁-C₆)alkyl-,amino(C₁-C₆)alkyl-, (C₁-C₆)alkylamino(C₁-C₆)alkyl-, and((C₁-C₆)alkyl)₂amino(C₁-C₆)alkyl.

[0089] Further aspects of the invention are described in accord with theDetailed Description of the invention which follows directly.

DETAILED DESCRIPTION OF THE INVENTION

[0090] According to the practice of the present invention, the secretionof growth hormone from cells (such as those of the anterior pituitary)is facilitated by inhibiting the somatostatin-induced (and G-proteincoupled) mechanisms that naturally oppose both calcium ion and cyclicAMP-mediated signals that otherwise trigger fusion with the cellmembrane of cytoplasmic granule structures that contain growth hormone,and the subsequent release (secretion) of GH.

[0091] The present invention provides an effective approach to thetreatment of frailty in older persons, which may be caused, in whole orpart, by insufficient levels of growth hormone (GH), or impairment ofany of several downstream physiological effects normally associated withgrowth hormone secretion. It is generally recognized that GH isimportant to the maintenance of connective and muscle tissue in adults,and may help, to some extent, to increase muscle mass. Thus growthhormone may be used to assist elderly patients even when growth hormonelevels per se are not the cause of, for example, weakness, or attritionof muscle and connective tissues. The practice of the invention benefitsother patients, such as children, when it can be demonstrated thatsecretion of growth hormone is inadequate, but is subject toenhancement. Deficiency in GH secretion, or resultant GH activity, mayarise in several ways. For example, the gene sequence that encodes GHmay be expressed in the nucleus at subnormal levels, processing ofresultant RNA transcript or nascent polypeptide may be defective, orfusion of cytoplasmic GH storage granules with the cell membrane (withresultant release of GH) may be defective. Additionally, the patient maypossess an allele of the GH gene that encodes a mutant protein havingless biological activity. Alternatively, there may be an underlyingdeficiency of GHRH, or a defect in the GHRH receptor, or defects in thethe GHRP receptor or deficiency of its endogenous ligand, or inrespective signalling mechanisms. Additionally, there may be an excessof somatostatin. In all such cases, the resultant physiologicaldeficiency can be treated by administration of the pharmaceuticalcompounds of the invention.

[0092] In a further aspect of the invention, the performance and growthrate of non-human mammals, such as livestock, is enhanced by appropriateadministration of the compounds disclosed herein. Additionally,companion animals, and particularly older companion animals also benefitupon administration of the present compounds.

[0093] Although the compounds of the present invention act to indirectlyfacilitate release of mature growth hormone from the cytoplasmic storagegranules of cells, additional therapeutic substances are known that candirectly enhance such secretion, and further, can indirectly enhanceproduction of growth hormone by via enhanced expression of GH-encodingDNA in the cell nucleus. In this regard, both growth hormone releasingpeptide (GHRP) and growth hormone releasing hormone (also known asgrowth hormone releasing factor, GHRH/GRF) which act to release GH fromcytoplasmic storage granules have been mentioned. Since the release ofGH from such granules has been implicated as a signal triggeringproduction of additional GH protein in the cells, it is expected that GHlevels may be properly maintained in patients using a “push-pull”approach.

[0094] Accordingly, a further preferred example of the inventionprovides for the co-administration of the somatostain-antagonistcompounds of the present invention and GHRP or GHRH, or other substancesof like effects. Medical treatment with GHRP (or GHRH) alone isdescribed in the following representative publications: M. Thorner etal., Journal Of Clinical Endocrinology And Metabolism, 81(3), pp.1189-1196, 1996; S. G. Celia et al., Peptides, 16(1), pp. 81-86, 1995;M. A. Bach et al., Journal Of The American Geriatrics Society, 44(9),S10, 1996; and J. A. Aloi et al., Journal Of Clinical Endocrinology AndMetabolism, 79(4), pp. 943-949, 1994.

[0095] Finally, since growth hormone is very labile, and its half-lifein the body is very short, it is difficult to provide a safe dosingprogram for direct administration of growth hormone itself, which avoidswide swings in circulating levels of the hormone. Current sustainedrelease technologies for direct administration of growth hormone can beimproved upon. In this regard, the practice of the present invention isparticularly valuable to the clinician, since by only indirectly raisingGH levels, the hormone's release profile remains, at least in part,under the control of the body's own regulatory feedback systems, andfluctuations in the levels of circulating GH are damped over time.

[0096] In the preferred practice of the invention, compounds showselectivity for the sst2 receptor compared with other receptor subtypes,for example sstl, sst3, sst4 and sst5. This selectivity minimizes thechance that other molecular biological or biochemical pathways will beadversely affected while growth hormone secretion is being upregulated.Most preferably, the affinity of a compound for the sst2 type receptorshould be at least about 10 times greater than for receptors of theother sst-subtypes.

[0097] It should be noted that the compounds of the invention may workby more than one mechanism, including those unrelated to interaction atan sst-type receptor, and the utility of the present compounds in thepractice of the invention, including for use in treating other diseasestates not particularly mentioned herein, is not limited by anyparticular theory as desrcibed herein or by those theories that isgenerally recognized by those skilled in the art.

[0098] Additionally, the compounds of the present invention may interactbeneficially with sst-type receptors other than sst2, and may providetherapeutic benefits by acting as somatostatin agonists, rather thanantagonists, at sst2 or other sst-type receptors. Various types ofsomatostain agonists are well known in the art, and the capacity of acompound of the present invention to act as an agonist, an antagonist,or as either, depending on physiological circumstances, can be predictedfrom the assays which are known in the art and/or described below. Forexample, measurement of cyclic-AMP, growth hormone release,microphysiometry responses, cell proliferation or protein kinaseactivity can be measured in cultured pituitary cells, cell lines orother cells such as neuroblastoma cells that express somatostatinreceptors, and cells transfected with recombinant somatostatinreceptorsincluding transfected yeast cells. (Y. C. Patel et al.,Biochemical & Biophysical Research Communications, 198(2), pp. 605-612,1994; M. G. Cattaneo et al., FEBS Letters, 397(2-3), pp. 164-168, 1996;J. A. Koenig et al., British Journal of Pharmacology, 120(1), pp. 45-51,1997; D. Djordjijevic et al., Endocrinology, 139(5), pp. 2272-2277,1998; W. R. Baumbach et al., Molecular Pharmacology, 54(5), pp. 864-73,1998.

[0099] Generally, somatostatin or agonists thereof demonstrateinhibitory activity, hence a stimulus is first applied (e.g. forskolinfor cyclic-AMP) and the inhibitory effect of somatostatin observed.Antagonists reverse the inhibitory effects of somatostatin.

[0100] Somatostatin agonists are recognized as useful therapeutics inthe treatment of diabetes, for example, see H. Gronbaeck et al., Prog.Basic Clin Pharmacol. (Basel), 10, pp. 103-128, 1996. Somatostatinagonists are also recognized (see WO 98/44922) as useful therapeutics inthe treatment of, for example, diabetic retinopathy, acromegaly,rheumatoid arthritis, neuropathic and visceral pain, irritable bowelsyndrome, Crohn's disease, and are useful to inhibit cell proliferationassociated with cancer, and to prevent restenosis following angioplasty.

[0101] Additionally, it has been determined that compounds havingaffinity for sst2 receptors also have affinity for receptors such asmcr4 and MCH. sst2 receptors and MCH receptors are also >50% homologous.Thus the compounds of the present invention may also be used to treatmedical conditions mediated through such other receptors.

[0102] As aforementioned. the compounds of this invention include allconformational isomers (e.g., cis and trans isomers, whether or notinvolving double bonds), tautomers, and all optical isomers of compoundsof the formula I (e.g., enantiomers and diastereomers), as well asracemic, diastereomeric and other mixtures of all such isomers. Withrespect to the design of the compounds of the invention, particularfeatures involving conformational and optical isomerism are of note.

[0103] In the below structure of a compound of formula (I), it ispreferred that the Z group thereof have the following stereospecificity

[0104] Thus, the Z group defines an L-amino acid, preferably selectedfrom the group consisting of L-tryptophanyl, L-histidinyl,L-3-methylhistidinyl, L-phenylalaninyl-, L-diphenylalaninyl-,L-3-fluorophenylalaninyl-, L-2-fluorophenylalaninyl-,L-4-fluorophenylalaninyl-, and L-tyrosinyl-, and which is mostpreferably, L-tryptophanyl.

[0105] It is less preferred that group Z have the followingstereospecificity

[0106] wherein the Z group defines a D-amino acid; however, in thiscase, use of D-tryptophanyl- is highly preferred.

[0107] In the below structural component of a compound of formula (I),it is preferred that the W group thereof have a stereospecificity at theindicated position (which corresponds to the α-carbon of an aminoacids), such that L-amino acids, or other structures having the sameabsolute stereospecificity, are defined.

[0108] In preferred examples, the W group defines an L-lysine group or a(C₁-C₈)alkyl ester thereof, or an L-arginine group or a (C₁-C₈)alkylester thereof, and in a highly preferred example there is defined a(C₁-C₈)alkyl ester of L-lysine. Additionally, the W group can define anL-diaminopimelic, L-canavanine, L-ornithine, L-2,4-diaminobutyric,L-5-hydroxylysine, L-epsilon-N-methyllysine, L-histidine, orL-3-methylhistidine group.

[0109] Additionally, L-lysine is preferably selected to provide the “W”component, when Trp derivatives (whether L or R) are used to provide the“Z” component.

[0110] L-Arginine is preferably selected to provide the “W” componentwhen Phe (or a derivative thereof such as 2-fluorophenylalaninyl-,3-fluorophenylalaninyl-, 4-fluorophenylalaninyl- or diphenylalaninyl-)is used to provide the “Z” component. In this case, the stereochemistryprovided within Phe, or a derivative thereof, should correspond to thatof L-amino acids, if possible.

[0111] Additionally, many of the groups of the present compounds may beoptionally substituted. As aforementioned, such substituents contributeproperties useful to production, storage, or use of the inventivecompounds as pharmaceuticals, or at least does not substantially negatetheir pharmacological activity. It will be appreciated that selection ofoptional substituents is further guided by principles recognized in theart, and/or is capable of validation through the use of the assaysdescribed in the present specification.

Pharmaceutical Formulations

[0112] The compounds of the present invention that are basic in natureare capable of forming a wide variety of different salts with variousinorganic and organic acids. Although such salts must bepharmaceutically acceptable for administration to animals, it is oftendesirable in practice to initially isolate the compound of the presentinvention from the reaction mixture as a pharmaceutically unacceptablesalt and then simply convert the latter back to the free base compoundby treatment with an alkaline reagent and subsequently convert thelatter free base to a pharmaceutically acceptable acid addition salt.The acid addition salts of the base compounds of this invention arereadily prepared, for example, by treating the base compound with asubstantially equivalent amount of the chosen mineral or organic acid inan aqueous solvent medium or in a suitable organic solvent, such asmethanol or ethanol. Upon careful evaporation of the solvent, thedesired solid salt is readily obtained. The desired acid salt can alsobe precipitated from a solution of the free base in an organic solventby adding to the solution an appropriate mineral or organic acid.

[0113] Those compounds of the present invention that are acidic innature, are capable of forming base salts with various pharmacologicallyacceptable cations. Examples of such salts include the alkali metal oralkaline-earth metal salts and particularly, the sodium and potassiumsalts. These salts are all prepared by conventional techniques. Thechemical bases which are used as reagents to prepare thepharmaceutically acceptable base salts of this invention are those whichform non-toxic base salts with the acidic compounds of the presentinvention. Such non-toxic base salts include those derived from suchpharmacologically acceptable cations as sodium, potassium calcium andmagnesium, etc. These salts can easily be prepared by treating thecorresponding acidic compounds with an aqueous solution containing thedesired pharmacologically acceptable cations, and then evaporating theresulting solution to dryness, preferably under reduced pressure.Alternatively, they may also be prepared by mixing lower alkanolicsolutions of the acidic compounds and the desired alkali metal alkoxidetogether, and then evaporating the resulting solution to dryness in thesame manner as before. In either case, stoichiometric quantities ofreagents are preferably employed in order to ensure completeness ofreaction and maximum yields of the desired final product.

[0114] In a preferred example of the invention, the compounds of thepresent invention may be formulated with additional pharmaceuticallyactive substances that directly or indirectly facilitate production andstorage in cells of additional growth hormone, or precursor polypeptidesthereof, or release of GH. Such additional substances include growthhormone releasing peptide (GHRP), growth hormone releasing hormone(GHRH), pituitary adenylate cyclase activating polypeptide (PACAP),dopaminergic agonists (e.g. bromocriptine), beta-adrenergic agonists(e.g. isoproterenol) and alpha 1-adrenergic agonists (e.g. methoxamine).For background information see E. O Soyoola et al., Proceedings of theSociety for Experimental Biology & Medicine, 207(1), pp. 26-33, 1994; V.Locatelli et al., Pediatric Research, 36(2), pp. 169-74, 1994; and B.Velkeniers et al., Journal of Endocrinology, 143(1), pp. 1-11, 1994.

[0115] Equivalently, the additional pharmaceutically active substancesmay be provided as a separate formulation which is co-administered, oradministered at some other timepoint(s) in the course of treatment.

[0116] This invention also encompasses pharmaceutical compositionscontaining prodrugs of compounds of the formula I. This invention alsoencompasses methods of treating or preventing disorders that can betreated or prevented by decreasing the levels of somatostatin comprisingadministering prodrugs of compounds of the formula I. Compounds offormula I having free amino, amido, hydroxy or carboxylic groups can beconverted into prodrugs. Prodrugs include compounds wherein an aminoacid residue, or a polypeptide chain of two or more (e.g., two, three orfour) amino acid residues which are covalently joined through peptidebonds to free amino, hydroxy or carboxylic acid groups of compounds offormula I. The amino acid residues include the 20 naturally occurringamino acids commonly designated by three letter symbols and alsoinclude, 4-hydroxyproline, hydroxylysine, demosine, isodemosine,3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid,citrulline, homocysteine, homoserine, ornithine and methionine sulfone.Prodrugs also include compounds wherein carbonates, carbamates, amidesand alkyl esters which are covalently bonded to the above substituentsof formula I through the carbonyl carbon prodrug sidechain.

[0117] One of ordinary skill in the art will also appreciate that whenusing the compounds of the invention in the treatment of a specificdisease, that the compounds of the invention may be combined withvarious existing therapeutic agents used for that disease, or for othermetabolically related or unrelated disease states that may occursimultaneously. As aforementioned, the additional pharmaceuticallyactive substances may be provided as a separate formulation which isco-administered, or administered at some other timepoint(s) in thecourse of treatment.

[0118] The compounds of the invention can also be used in combinationwith existing therapeutic agents such as the above mentioned growthhormone secretagogues for the treatment of growth hormone deficiency.

[0119] For the treatment of growth hormone deficiency, the compounds ofthe invention may be combined with agents such as recombinant growthhormone which is marketed by Genentech and licensees (Neutropin,Genotropin and Protropin), Bio-Technology General and licensees(Zomacton, Growject, Elvetium and SciTropin), Novo Nordisk(Norditropin), LG Chem (Eutropin), Ares Serono (Saizen and Serostim),Eli Lilly Co (Humatrope), Monsanto (Posilac brand of bovine growthhormone) and Alpharma (Reporcin brand of swine growth hormone).

[0120] The compounds of the invention can also be used in combinationwith existing therapeutic agents such as Geref (sermorelin, GHRH) fromSerono Laboratories Inc.

[0121] The compounds of the invention can also be used in combinationwith existing therapeutic agents such as anabolic steroids, e.g.androisoxazol androstanolone (DHT, dihydrotestosterone, Stanolone,Anabolex, Andractrim), bolandiol, bolasterone, bolazin, boldenone(Equipoise), calusterone, clostebol (chlortestosterone, Steranabol, AlfaTrofodermin, Dermanabol, Trofodermin, Trofoseptine), danazol (Cyclomen,Danocrine), dehydrochlormethyltestosterone (turinabol, Oral-turinabol),drostanolone (dromostanolone, Drolban, Masterid, Masteril, Masteron,Metormon, Premastril), estradiol, ethylestrenol, fluoxymesterone(Halotestin, Ora-Testryl, Android-F), formebolone, furazabol (Miotolon),mestanolone, mesterolone (Proviron, Pluriviron), methandienone(methandrostenolone, Metaboline), methandriol, methenolone (Primobolan),methyltestosterone (Methandren, Premarin with methyltestosterone,Android, Oreton, Testred, Methyltestosterone tabs, Geri-Bons, Geri-tabs,Dermonal), mibolerone (Cheque), nandrolone (Deca-Durabolin, Durabolin,Nandrabolin, Anabolin, Androlone, Hybolin, Nandrobolic), norclostebol,norethandrolone (Nilevar), oxabolone, oxandrolone (Anavar), oxymesterone(Oranabol), oxymetholone (Anapolon 50, Androyd, Anadrol, Anasteron,Dynasten, Oxitosona, Plenastril, Synasteron, Zenalosyn), penmesterol,prasterone, quinbolone, stanozolol (Winstrol, Winstrol-V, Stromba,Strombaject), stenbolone, testosterone (Malogen, Delatestryl, Malogen,Neo-pause, PMS-testosterone Enanthate, Andriol, Duogex, Neo-Pause,Climacteron, Orchisterone-P, Oreton, Anadiol, Anatest,Testos-100,Heifer-aid, Synovex-H), tibolone, trenbolone (Parabolan,Finaject) or zeranol.

[0122] The compounds of the invention can also be used in combinationwith existing therapeutic agents such as Somazon (mecasermin,recombinant insulin-like growth factor I) from Fujisawa.

[0123] For the treatment of older patients with osteoporosis, suitableagents to be used in combination with the compounds of the inventioninclude standard non-steroidal anti-inflammatory agents (hereinafterNSAID's) such as piroxicam, diclofenac, propionic acids such asnaproxen, flubiprofen, fenoprofen, ketoprofen and ibuprofen, fenamatessuch as mefenamic acid, indomethacin, sulindac, apazone, pyrazolonessuch as phenylbutazone, salicylates such as aspirin, COX-2 inhibitorssuch as celecoxib and rofecoxib, analgesics and intraarticular therapiessuch as corticosteroids and hyaluronic acids such as hyalgan andsynvisc.

[0124] The compounds of the present invention may also be used incombination with osteoporosis agents such as lasofoxifene, raloxifene,droloxifene or fosomax and immunosuppressant agents such as FK-506 andrapamycin.

[0125] The compounds of the present invention may also be used incombination with immunostimulant agents for the treatment of reducedimmune function.

[0126] The compounds of the present invention may also be used incombination with fertility agents such as human menopausal gonadotropin,chorionic gonadotropin, follicle stimulating hormone, nafarelin,triptorelin, cetrorelix, and ganirelix for the treatment of infertility.

[0127] The compounds of the present invention may also be used incombination with AIDS therapies for the treatment of AIDS-relatedcomplex.

[0128] The compounds of the present invention may also be used incombination with anti-tumor necrosis factor agents such as infliximab(TNF monoclonal antibody) or etanercept (soluble TNF receptor) for thetreatment of cachexia.

[0129] The compounds of the present invention may also be used incombination with potassium channel blockers, beta-blockers,anticoagulants or vasodilators for the treatment of heart disease.

[0130] The compounds of the present invention may also be used incombination with angiotensin II (ATII) antagonists or erythropoietin forthe treatment of renal failure.

[0131] For administration to livestock, the compounds of the inventionmay also be used in combination with feed additives such as antibiotics(e.g. monensin, lasalocid, salinomycin, semduramicin, narasin,maduramicin, virginiamycin, polymixin, efrotomycin, avoparcin,lincomycin, bacitracin, bambermycins, novobiocin, erythromycin,oleandomycin, streptomycin, tylosin, penicillin, tetracycline,oxytetracycline, chlortetracycline, carbadox, olaquindox, neomycinmoenomycin avilamycin and flavophospholipol), repartitioning agents,beta-agonists (e.g. Paylean, ractopamine, from Elanco), and alsoamiterol, bambuterol, bitolterol, broxaterol, buphenine, carbuterol,cimaterol, clenbuterol, clorprenaline, colterol, denopamine,dioxethedrine, dioxifedrine, dobutamine, dopexamine, doxaminol,etanterol, fenoterol, flerobuterol, formoterol, hexoprenaline, ibuterol,imoxiterol, isoetarine, isoxsuprine, levisoprenaline, mabuterol,mesuprine, metaterol, methoxyphenamine, nardeterol, orciprenaline,picumeterol, pirbuterol, prenalterol, procaterol, protokylol,quinprenaline, rimiterol, ritodrine, salbutamol, salmeterol,terbutaline, tretoquinol, tulobuterol, xamoterol and zilpaterol.

[0132] The compositions of the present invention may be formulated in aconventional manner using one or more pharmaceutically acceptablecarriers. Thus, the active compounds of the invention may be formulatedfor oral, buccal, intranasal, parenteral (e.g., intravenous,intramuscular or subcutaneous) or rectal administration or in a formsuitable for administration by inhalation or insufflation. The activecompounds of the invention may also be formulated for sustaineddelivery.

[0133] For oral administration, the pharmaceutical compositions may takethe form of, for example, tablets, chewable tablets, or capsulesprepared by conventional means with pharmaceutically acceptableexcipients such as binding agents (e.g., pregelatinized maize starch,polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g.,lactose, microcrystalline cellulose or calcium phosphate); lubricants(e.g., magnesium stearate, talc or silica); disintegrants (e.g., potatostarch or sodium starch glycolate); or wetting agents (e.g., sodiumlauryl sulphate). The tablets may be coated by methods well known in theart. Liquid preparations for oral administration may take the form of,for example, solutions, syrups or suspensions, or they may be presentedas a dry product for constitution with water or other suitable vehiclebefore use. Such liquid preparations may be prepared by conventionalmeans with pharmaceutically acceptable additives such as suspendingagents (e.g., sorbitol syrup, methyl cellulose or hydrogenated ediblefats); emulsifying agents (e.g., lecithin or acacia); non-aqueousvehicles (e.g., almond oil, oily esters or ethyl alcohol); andpreservatives (e.g., methyl or propyl p-hydroxybenzoates or sorbicacid).

[0134] For buccal administration, the composition may take the form oftablets or lozenges formulated in conventional manner, or blended withpetfood or animal feed, or as a pre-mix for blending with animal feed.

[0135] The active compounds of the invention may be formulated forparenteral administration by injection, including using conventionalcatheterization techniques or infusion. Formulations for injection maybe presented in unit dosage form, e.g., in ampules or in multi-dosecontainers, with an added preservative. The compositions may take suchforms as suspensions, solutions or emulsions in oily or aqueousvehicles, and may contain formulating agents such as suspending,stabilizing and/or dispersing agents. Alternatively, the activeingredient may be in powder form for reconstitution with a suitablevehicle, e.g., sterile pyrogen-free water, before use.

[0136] The active compounds of the invention may also be formulated inrectal compositions such as suppositories or retention enemas, e.g.,containing conventional suppository bases such as cocoa butter or otherglycerides.

[0137] For intranasal administration or administration by inhalation,the active compounds of the invention are conveniently delivered in theform of a solution or suspension from a pump spray container that issqueezed or pumped by the patient or as an aerosol spray presentationfrom a pressurized container or a nebulizer, with the use of a suitablepropellant, e.g., dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol, the dosage unit may be determined byproviding a valve to deliver a metered amount. The pressurized containeror nebulizer may contain a solution or suspension of the activecompound. Capsules and cartridges (made, for example, from gelatin) foruse in an inhaler or insufflator may be formulated containing a powdermix of a compound of the invention and a suitable powder base such aslactose or starch.

[0138] A proposed dose of the active compounds of the invention fororal, parenteral or buccal administration to the average adult human is0.1 to 100 mg of the active ingredient per unit dose which could beadministered, for example, 1 to 4 times per day.

[0139] Aerosol formulations for treatment of the conditions referred toabove in the average adult human are preferably arranged so that eachmetered dose or “puff” of aerosol contains 20 μg to 1000 μg of thecompound of the invention. The overall daily dose with an aerosol willbe within the range 0.1 mg to 100 mg. Administration may be severaltimes daily, for example 2, 3, 4 or 8 times, giving for example, 1, 2 or3 doses each time.

[0140] Injected doses are preferably administered from about once amonth, up to about 1 to 4 times per day, at an individual dosing of0.01-1mg/kg (of active ingredient) and may be intramuscular,intravenous, or subcutaneous, for example.

[0141] As is well recognized, the precise dose, and method and timing ofadministration thereof, are capable of determination by those skilled inthe art, and depend upon numerous factors including the activity of thetherapeutic compound, the properties of the formulation thereof, thenature and location of the target tissue, and the particulars of thedisease state as it exists in a particular patient. Additionally, whenthe compounds of the present invention are administered to a patientwith additional pharmaceutically active substances, one or morepharmaceutical compositions may be used to deliver all of the activeagents, which may be administered together, or at different times, asdetermined by those skilled in the pharmaceutical or medical arts.

[0142] The following reaction schemes illustrate preparation ofcompounds of the present invention. It will be appreciated that thegroups represented by letters (“R” groups, and the like) in the Schemesdo not always correspond with similarly defined component groups of theformula (I) compounds themselves, since certain functionalities of thereactants are modified when the products are formed. Thus, to facilitatepresentation of the schemes, R¹ and R^(1′), as referred to below,correspond to R¹ and R^(1′) as used throughout the Specification indefining the compounds of formula (I), whereas Ar₁, Ar₂, Ar₃, and R₂represent structures that overlap with those as elsewhere defined, as isreadily apparent upon inspection. For example, Ar₁, Ar₂, and Ar₃ do notcorrespond to “A”, but rather represent any (C₆-C₁₀)aryl or(C₁-C₉)heteroaryl group as defined herein. R₂ typicially represents analkyl group, whether primary, secondary, or tertiary, but can also bearyl or benzyl.

General Reaction Conditions

[0143] Generally speaking, the compounds of the present invention aremade by a series of “condensation” reactions in which certain reactivegroups are appropriately protected, and the sequence of condensation iscontrolled. Schemes I and II demonstrate that the component materialsmay be coupled in more than one sequence. Referring to Scheme I, thecompounds of formula 1 which include an L-arginine moiety, may beprepared from the compounds of formula 2 by removal of theguanidine-protecting nitro group via a reduction reaction using formicacid as reducing agent in the presence of palladium on carbon. In atypical procedure, the reaction mixture is stirred overnight undernitrogen, filtered, and the solvent then removed under reduced pressure.Recovered material may then be triturated with diethylether, and driedovernight under high vacuum to yield the final product. Although nitrois the preferred protecting group, Boc may also be used, in which casesuitable reaction conditions for deprotection are stirring withtrifluoracetic acid or hydrochloric acid.

[0144] Again referring to Scheme I, the compounds of formula 2 may beprepared by condensation of the compounds of formulas 3 and 4, forexample in the presence of 1,3-dimethylaminopropyl-3-ethylcarbodiimidehydrochloride hydroxybenzotriazole and dimethylaminopyridine. Thereaction mixture may then be washed successively with portions of 10%aqueous hydrochloric acid solution, followed by washes with 50%saturated sodium bicarbonate solution, and saturated brine. Theresulting product 2 may then be dried over anhydrous magnesium sulfate,filtered, and the solvent removed under reduced pressure.

[0145] In a preferred example of the invention, compounds of formulas 3and 4 include amino acid moieties which confer peptide-like structure onthe final product compounds, consistent with their activity assomatostain analogs. Compound 3 may represent one of several suitablyprotected amino acids, for example, comprising a lysine, arginine,histidine, or ornithine residue, wherein the carboxyl group thereof isprotected, for example, by a suitable alkyl group (R₂). Thestereospecificity at the subregion of the product compound defined as“W” herein is determined by the stereospecificity of the participatingamino acid. In the practice of the invention, stereospecificitycorresponding to an L-amino acid is preferred.

[0146] Note that L-lysine is preferably selected to provide the “W”component, when Trp derivatives (whether L or R) are used to provide the“Z” component.

[0147] L-arginine is preferably selected to provide the “W” componentwhen Phe (or derivatives thereof such as 3-fluorophenylalaninyl- ordiphenylalaninyl-) is used to provide the “Z” component. In this case,the stereochemistry provided within Phe, or a derrivative thereof,should correspond to that of L-amino acids, if possible.

[0148] The deprotection that occurs in step 2→1 can be accomplished witha different agent, for example TFA, or depending on the amino acidmoiety contributed by compound 3, a different deprotection strategy canbe employed. For example in the case where the amino acid moiety islysine, or a lysine-like structure, protection of the alkylamine sidechain may be accomplished by providing compound 3 as a BOC derivative,

[0149] with subsequent coupling, followed by hydrolysis in HCl.

[0150] Compounds 4 are readily prepared from compounds 5 by hydrolysisunder alkaline conditions, most preferably using LiOH in methanol/water.

[0151] Compounds 5 are prepared by reaction to form an amide linkagebetween compounds 6 and 7. It will be seen that compound 5 contributesthe Z subregion of the final product 1, and is responsible for itsstereospecificity. Although group Ar₂ therein may be any (C₆-C₁₀)arylgroup or (C₁-C₉)heteroaryl group as those terms are defined in theSpecification, it is again preferred that Ar₂ permit the Z subregion tocontribute an amino acid moiety, for example, a tryptophanyl,histidinyl, phenylalaninyl or tyrosinyl group. In the practice of theinvention, stereospecificity corresponding to an L-amino acid ispreferred, although use of D-trypophanyl is also preferred.

[0152] Numerous recognized procedures can be used to react compounds 6and 7 as herein required. For example, an alkyl ester of compound 6 canbe reacted with a compound of formula 7 in triethylamine/methylenechloride with overnight stirring with a dehydrating agent such asdicyclohexylcarbodiimide, or more preferably, with hydroxybenzotriazole,4-dimethylaminopyridine, and 1,3-dimethylaminopropyl-3-ethylcarbodiimidehydrochloride in methylene chloride. The solution may then be washedsequentially with sufficient portions of 10% hydrochloric acid, 50%saturated sodium bicarbonate, and saturated brine. The product may thenbe dried over anhydrous magnesium sulfate, filtered, and the solventremoved, for example.

[0153] It will be appreciated that groups R¹, R^(1′) and Ar₁ (and thereactants that provide them) are selected to permit all of the productcompounds of the invention. In this regard, the following structures arerepresentative of those that may be used in place of compound 7 in thepractice of the invention, so the moieties [A—G] in the compounds offormula (I) are defined.

[0154] wherein Ar₁ (or Ar₃) is any (C₆-C₁₀)aryl or (C₁-C₉)heteroarylgroup, and the synthesis of the resultant reactants will be apparent tothose skilled in the art. For example, the above structures can be madefrom the corresponding amino acids.

[0155] As aforementioned, since the general reaction scheme hereininvolves a series of “condensations”, it will be appreciated that theillustrated reactions may be conducted in a different sequence, orequivalent reaction steps can be substituted. Scheme II is one suchadditional possibility, and illustrations of its use are found in thenumbered Examples which follow.

[0156] Schemes III(a) and III(b) provide approaches to group “W” in thegeneral structure A—G—Z—W, where W is alternative (b)

[0157] wherein

[0158] Q is selected from the group consisting of (C₆-C₁₀)aryl,(C₁-C₉)heteroaryl, (C₃-C₁₀)cycloalkyl, and (C₃-C₁₀)heterocycloalkyl; and

[0159] R⁷, R⁸, and R⁹ are each independently selected from H,(C₁-C₈)alkyl-, and phenyl(CH₂)—, wherein said alkyl and phenyl groupsare optionally substituted.

[0160] Schemes III(a) and III(b) outline representative syntheses ofcomponent W wherein each of R⁷, R⁸ and R⁹ is H, and Q is, for example,either cyclohexane or pyridine. Numerous equivalent schemes areavailable to the practitioner.

[0161] Referring first to Scheme I, product 14 of Scheme III(a), andsimilar compounds, can replace compounds of the formula 3, so thatcompound analogous to compounds 2 are prepared from compounds of formula4. Compounds analogous to those of formula 1 are then prepared fromcompounds of analogous to those of formula 2 by removal of theprotecting BOC group under acidic conditions.

[0162] Referring to Scheme III(a), compounds of formula 14 may beprepared from compounds of 15 by reduction with hydrogen underappropriate conditions. Compounds of formula 15 may be prepared fromcompounds of formula 16 via reaction using NaN₃ to displace the mesylateester of compounds 16. Compounds 16 may be prepared from compounds 17with mesyl (methanesulfonyl) chloride under basic conditions, forexample, in triethylamine/dichloromethane at 0° C., in good yield.Compounds 17 may be prepared from compounds 18 by reduction at thecarboxyl group thereof using BH₃. Compounds 18, having thestereospecificity indicated in Scheme II(a), are prepared from racemiccompounds 20 by chiral resolution with stereospecificα-methylbenzylamine, followed by selective purification, such as bycrystallization. Compounds 20 may be prepared from the correspondingaromatic compounds 21 by reduction with hydrogen, for example, underappropriate conditions. Compounds 21 in turn are prepared from thecorresponding (unprotected) compounds 22 by reaction with BOC anhydrideunder standard conditions. Finally, compounds 22 may be prepared fromavailable starting materials 23, by reduction of the cyano group withhydrogen over a Raney nickel preparation.

[0163] In Scheme III(b), advantage is taken of available startingmaterials to generate compounds of the formula 14′ in 2 steps, firstfrom compounds of formula 24 using BOC anhydride. Compounds 24 aregenerated from compounds of formula 25 by reduction of both cyanogroups, again with hydrogen and Raney nickel as catalyst.

EXAMPLES

[0164] The following are representative compounds of the invention.

Example 1

[0165]6-Amino-2-[2-[(biphenyl-4-ylmethyl)-amino]-3-(1H-indol-3-yl)-propionylamino]-hexanoicAcid Methyl Ester, Having the Indicated Stereospecificity.

[0166] Step 1

[0167] Wang resin (Arogel Wang, Argonaut Technologies, 170 mg, 0.39mmol/g. 0.066 mmol) was allowed to swell in 3 mL CH₂Cl₂ for 15 min, andwashed 3× (3 times) with 3 mL CH₂Cl₂. A solution of Fmoc-Lsy(Boc)-OH(128 mg, 0.26 mmol), DIC (38 uL, o.26 mmol), TEA (70 uL, 0.5 mmol) andDMAP (3 mg, 0.026 mmol) in 2.5 mL CH₂Cl₂ was added, and the mixture wasagitated by rotation for 1.5 h. The resin was then washed,consecutively, 3× with 3 mL CH₂Cl₂, 2× with 3 mL DMF, 2× with 3 mL EtOH,and finally 3× with 3 mL CH₂Cl₂. 3 mL of a 20% solution of piperidine inCH₂Cl₂ was then added, and the composition was agitated by rotation for1 h. The resin was then washed, consecutively, 3× with 3 mL CH₂Cl₂, 2×with 3 mL DMF, 2× with 3 mL EtOH, and 3× with 3 mL CH₂Cl₂. A solution ofFmoc-d-Trp-OH (110 mg, 0.26 mmol), ), DIC (38 uL, 0.26 mmol), TEA (70uL, 0.5 mmol) and DMAP (3 mg, 0.026 mmol) in 2.5 mL CH₂Cl₂ was thenadded, and the mixture was agitated by rotation for 1.5 h. The resin wasnext washed, consecutively, 3× with 3 mL CH₂Cl₂, 2× with 3 mL DMF, 2×with 3 mL EtOH, and then 3× with 3 mL CH₂Cl₂. 3 mL of a 20% solution ofpiperidine in CH₂Cl₂ was then added, and the mixture was agitated byrotation for 1 h. The resin was next washed, consecutively, 3× with 3 mLCH₂Cl₂, 2× with 3 mL DMF, 2× with 3 mL EtOH, and then 3× with 3 mLtoluene.

[0168] Step 2 Preparation of the Title Compound

[0169] 2.5 mL of 10% THF in toluene was added to the resin, followed bybiphenyl carboxaldehyde (50 mg). The composition was agitated byrotation for 1 hour, after which 0.5 mL 1M NaCHBH4 (in THF) was added,and rotation was continued for 2 h. The resin was then washed,consecutively, 3× with 3 mL CH₂Cl₂, 2× with 3 mL DMF, 2× with 3 mL EtOH,and 3× with 3 mL of CH₂Cl₂. The composition was then subject to blowdrying under N₂, and then transfered to a 4 dram vial. 3 mL of 9:1:1MeOH, DMF, TEA solution was added, and the compostion mixed on anorbital shaker at 50 C for 2.5 days. The resin was then filtered andwashed, 2× with 3 mL CH₂Cl₂, followed 3× with 3 mL EtOH. The resultingsolid was evaporated and passed through an SiO₂ plug with EtOAc todeliver 10 mg product. The product was then dissolved into 2 mL 20%conc. HCl in EtOH, and then stirred at room temperature for 30 min. Theresulting HCl salt was evaporated and tritrated with ether to afford 9mg product. MS/+: 613.2; 1H NMR: 7.10 (m, 2H), 4.21 (m, 1H), 3.62 (s,3H), 1.83 (m, 2H).

[0170] It should be noted that if the L-lysinyl residue in the backboneof the exemplified compound is replaced with a residue provided by2,4-diaminobutyric acid, the compound was substantially less active inassays. However, replacement by L-ornithinyl- resulted in activecompounds.

Example 2

[0171]2-{3-(3-Fluoro-phenyl)-2-[2-(toluene-4-sulfonylamino)-acetylamino]-propionylamino}-5-guanidino-pentanoicAcid Methyl Ester, Having the Indicated Stereospecificity.

[0172] Step 1 Preparation of 3-F-Phe-Arg(NO₂)-OMe

[0173] To a solution of 2.00 gm of BOC-3-F-Phe-OH (7.06 mmol), 2.09 gmof Arg(NO₂)-OMe HCl (7.77 mmol), 1.05 gm of hydroxybenzotriazole and2.58 gm of 4-dimethylaminopyridine in 50 mL of methylene chloride wasadded 1.5 gm of 1,3-dimethylaminopropyl-3-ethylcarbodiimidehydrochloride. After stirring for 15 hours 100 mL more methylenechloride was added to the reaction, and it was washed three times with100 mL portions of 10% aqueous hydrochloric acid solution, twice with100 mL of 50% saturated sodium bicarbonate solution, once with 100 mL ofsaturated brine, dried over anhydrous magnesium sulfate, filtered, andthe solvent removed under reduced pressure to yield 2.96 gm of product.This was dissolved in 100 mL of 10% trifluoroacetic acid in methylenechloride, stirred for 2 hours, and the solvent removed rapidly underreduced pressure. The material was triturated with diethyl ether anddried under high vacuum to yield product.

[0174] Step 2 Preparation of the Title Compound

[0175] To a solution of 104 mg of tosylglycine (0.456 mmol), 273 mg of3-F-Phe-Arg(NO₂)-OMe HCl (0.684 mmol), 93 mg of hydroxybenzotriazole(0.689 mmol) and 167 mg of 4-dimethylaminopyridine (1.37 mmol) in 20 mLof methylene chloride was added 137 mg of1,3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (0.684 mmol).After stirring for 15 hours 100 mL more methylene chloride was added tothe reaction, and it was washed three times with 20 mL portions of 10%aqueous hydrochloric acid solution, twice with 20 mL of 50% saturatedsodium bicarbonate solution, once with 20 mL of saturated brine, driedover anhydrous magnesium sulfate, filtered, and the solvent removedunder reduced pressure. This material was dissolved in 60 mL ofmethanol, 300 mg of 10% palladium on carbon was added under nitrogen,followed by 2.5 mL of formic acid. The mixture was stirred overnightunder nitrogen, filtered, the solvent removed under reduced pressure,the material triturated with diethyl ether, and dried overnight underhigh vacuum to yield the product. This material can also be synthesizedby coupling a suitably protected arginine fragment with a suitablyprotected trptophan fragment, deprotecting the tryptophan amino group,condensing this material with tosylglycine, and deprotecting thearginine sidechain. ¹H NMR (CD₃OD): δ 4.65 (m, 1H); 4.42 (m, 1H); 3.72(s, 3H); 2.45 (s, 3H). MS: M+1=565

[0176] It should be noted if the glycinyl residue in the backbone of theexemplified compound is replaced with alaninyl (whether D- or L-), thecompound was substantially less active in assays. However, replacementby α-methylalaninyl- resulted in active compounds. The glycinyl residueis also usefully replaced by β-alanine and γ-aminobutyric acid.

Example 3

[0177]6-Amino-2-[2-[(biphenyl-4-carbonyl)-amino]-3-(1H-indol-3-yl)-propionylamino]-hexanoicAcid Methyl Ester, Having the Indicated Stereospecificity.

[0178]¹H NMR (CD₃OD): δ 4.32 (m, 1H); 3.39 (d, 1H); 3.63 (s, 3H); 2.87(m, 2H). MS: M+1=527

Example 4

[0179]2-{2-[(Biphenyl-4-carbonyl)-amino]-3,3-diphenyl-propionylamino}-5-guanidino-pentanoicacid methyl ester, having the indicated stereospecificity.

[0180]¹H NMR (CD₃OD): δ 5.45 (d, 1H); 4.55 (d, 1H); 4.25 (m, 2H); 3.49(s, 3H). MS: M+1=592

Example 5

[0181]6-Amino-2-[2-[(biphenyl-4-carbonyl)-amino]-3-(1H-indol-3-yl)-propionylamino]-hexanoicacid tert-butyl ester, having the indicated stereospecificity.

[0182] Step 1 Preparation of L-Trp-OMe 4-Biphenylcarbonylamide

[0183] Dissolve 3.45 gm (13.54 mmol) of L-Trp-Ome hydrochloride and 4.11gm (40.6 mmol) triethylamine in 500 mL of methylene chloride. Then add2.934 gm (13.54 mmol) of 4-biphenycarbonylchloride portionwise, andallow the reaction to stir overnight. The solution was then washed twicewith 100 mL portions of 10% hydrochloric acid, twice with 100 mLportions of 50% saturated sodium bicarbonate, once with 100 mL ofsaturated brine, dried over anhydrous magnesium sulfate, filtered, andthe solvent removed under reduced pressure to yield 4.83 gm (90%) ofproduct.

[0184] Step 2 Preparation of L-Trp-OH 4-Biphenylcarbonylamide L-Trp-Ome4-Biphenylcarbonylamide (4.83 gm, 12.12 mmole) was dissolved in 120 mLof methanol, then 2.543 gm (60.6 mmol) lithium hydroxide monohydrate in40 mL of water was added. The reaction was heated to 70 C to dissolveall of the contents, and after maintaining stirring at that temperaturefor 30 minutes the reaction was cooled to room temperature. The methanolwas removed by rotary evaporation, and the aqueous slurry was acidifiedto pH 2.0 with 10% aqueous hydrochloric acid. The solid was thenfiltered and dried overnight under vacuum to yield 3.79 gm (81%) ofproduct.

[0185] Step 3 Preparation of Title Compound as Trifluoroacetate Salt

[0186] To a solution of 100 mg of L-Trp-OH 4-Biphenylcarbonylamide (0.26mmol), 132 mg of Lys(Z)-OtBu HCl (0.39 mmol), 53 mg ofhydroxybenzotriazole (0.39 mmol) and 191 mg of 4-dimethylaminopyridine(1.56 mmol) in 40 mL of methylene chloride was added 150 mg (0.78 mmol)of 1,3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride. Afterstirring for 15 hours 100 mL more methylene chloride was added to thereaction, and it was washed three times with 30 mL portions of 10%aqueous hydrochloric acid solution, twice with 20 mL of 50% saturatedsodium bicarbonate solution, once with 20 mL of saturated brine, driedover anhydrous magnesium sulfate, filtered, and the solvent removedunder reduced pressure. The product was then dissolved in 10 mL ofmethylene chloride, 1 mL of triflouroacetic acid was added, and thereaction stirred for 3.5 hours. The solvent was then removed rapidlyunder reduced pressure, the product was triturated with diethyl ether,and dried under high vacuum overnight to yield 67 mg of product. Thismaterial can also be synthesized by coupling a suitably protected lysinefragment with a suitably protected tryptophan fragment, deprotecting thetryptophan amino group, condensing this material with biphenylcarbonylchloride, and deprotecting the lysine sidechain. ¹H NMR (CD₃OD): δ 4.36(m, 1H); 3.40 (m, 1H); 2.85 (m, 2H); 1.43 (s, 9H). MS: M+1=569

Example 6

[0187]6-Amino-2-[2-[(biphenyl-4-carbonyl)-amino]-3-(1H-indol-3-yl)-propionylamino]-hexanoicacid tert-butyl ester, having the indicated stereospecificity.

[0188]¹H NMR (CD₃OD): δ 4.18 (m, 1H); 3.45 (m, 1H); 2.78 (m, 2H); 1.40(s, 9H). MS: M+1=569

Example 7a

[0189]6-Amino-2-[2-(2-benzenesulfonylamino-2-methyl-propionylamino)-3-(1H-indol-3-(1H-indol-3-yl)-propionylamino]-hexanoicAcid Tert-butyl Ester, Having the Indicated Stereospecificity.

[0190] This was synthesized by couplingα-methylalaninebenzenesulfonamide (from α-methylalanine andbenzenesulfonyl chloride) with (L)Trp-Ome using1,3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride, methyl esterdeprotection with LiOH, coupling with Lys(Boc)-OtBu HCl using1,3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride, anddeprotecting with trifluoroacetic acid. ¹H NMR (CD₃OD): δ 4.38 (m, 1H);4.65 (m, 1H); 3.47 (d, 2H); 1.45 (s, 6H); 1.41 (s, 9H). MS: M+1=614.

Example 7b

[0191]6-Amino-2-[2-(2-benzenesulfonylamino-2-methyl-propionylamino)-3-(1H-indol-3-yl)-propionylamino]-hexanoicacid tert-butyl ester, having the indicated stereospecificity.

[0192] Synthetic details are as in Example 7a, except for use of(D)Trp-Ome.

Example 8

[0193]6-Amino-2-[2-{[4-(benzenesulfonylamino-methyl)-cyclohexanecarbonyl]-amino}-3-(1H-indol-3-yl)-propionylamino]-hexanoicAcid Tert-butyl Ester.

[0194] MS M+1=668.9.

[0195] The ability of compounds of formula (I), and the pharmaceuticallyacceptable salt, solvates or hydrate thereof (hereinafter referred to asthe compounds of the present invention) to act as somatostatinantagonists, or agonists, and consequently to demonstrate theireffectiveness in the treatment of disease states, is shown by thefollowing assays.

[0196] Biological Assays

[0197] Various types of somatostain agonists are well known in the art,and the capacity of a compound of the present invention to act as anagonist, an antagonist, or as either, depending on physiologicalcircumstances, can be predicted from the assays which are known in theart and/or described below. For example, measurement of cyclic-AMP,growth hormone release, microphysiometry responses, cell proliferationor protein kinase activity can be measured in cultured pituitary cells,cell lines or other cells such as neuroblastoma cells that expresssomatostatin receptors, and cells transfected with recombinantsomatostatin receptors including transfected yeast cells. (Y. C. Patelet al., Biochemical & Biophysical Research Communications, 198(2), pp.605-612, 1994; M. G. Cattaneo et al., FEBS Letters, 397(2-3), pp.164-168, 1996; J. A. Koenig et al., British Journal of Pharmacology,120(1), pp. 45-51, 1997; D. Djordjijevic et al., Endocrinology, 139(5),pp. 2272-2277, 1998; W. R. Baumbach et al., Molecular Pharmacology,54(5), pp. 864-73, 1998).

[0198] Generally, somatostatin or agonists thereof demonstrateinhibitory activity, hence a stimulus is first applied (e.g. forskolinfor cyclic-AMP) and the inhibitory effect of somatostatin observed.Antagonists reverse the inhibitory effects of somatostatin.

[0199] The ability of compounds of formula (I), and the pharmaceuticallyacceptable salt, solvates or hydrate thereof (hereinafter referred to asthe compounds of the present invention) to act as somatostatinantagonists, or agonists, and consequently to demonstrate theireffectiveness in the treatment of disease states, is shown by thefollowing assays.

Example 9 Bovine (“b”)sst2 Binding Assay

[0200] The present example describes an assay for binding ofpharmaceutically useful somatostatin agonists and antagonists at thebovine sst2 receptor.

[0201] The methods for culturing Neuro2A cells and measuring competitivebinding potency (IC₅₀) were similar to those described by J. A. Koeniget al., “Somatostatin receptors in Neuro2A neuroblastoma cells:operational characteristics”, British J. Pharmacol., 120, 45-51, 1997,with the following modifications.

[0202] Binding assays were conducted 72 hours after transientlytransfecting the Neuro2A cells with a plasmid (PCI-bsst2) containing aninsert coding for the bovine sst2 receptor, placed downstream of thecytomegalovirus promoter. In the transfection step, 6.5×10⁶ Neuro2Acells were added in 35 ml of media to each tissue culture flask (162 cm²surface area). The next day, transfection was conducted using Fugene 6(Boehringer Mannheim, 1 814 443) according to the manufacturer'sdirections. The Fugene 6 (30 μl/flask) was equilibrated with 8 μg ofPCI-bsst2 plasmid, and added to the Neuro2A cells in the absence offetal bovine serum. After 3 hours, fresh serum-containing media wasadded. The assay buffer was modified to contain 50 mM HEPES, 5 mM MgCl₂,1 mg/ml bovine serum albumin (BSA), 0.02 mg/ml bacitracin, and 10 μMeach of aprotinin, leupeptin and AEBSF. The transfected Neuro2A cellswere dissociated in the absence of trypsin/EDTA, in ice cold assaybuffer (5.5 ml/flask), and cells were homogenized in a 55 ml WheatonDounce homogenizer (15-20 strokes). Membrane preparations were stored inaliquots at −70° C. Competitive binding assays and separation of boundfrom free radioactivity were conducted in polyethyleneimine-soakedMillipore 96 Well GF/C Filterplates, (MAFC NOB10). An amount of membranewas used that bound approximately 20% of [¹²⁵I]-somatostatin 14 tracer(Amersham, IM161), which was added to all wells at 15,000 cpm/well(approximately 15 nCi/well). Somatostatin was included in eachexperiment as positive control, at 7 concentrations from 0.0042 to 1.667nM, and test compounds were included at 7 concentrations from 33 nM to13.33 μM. The reaction volume was 300 μl and the incubation wasconducted for 1 hour at 37° C. Non-specific binding was defined using0.83 μM somatostatin 14. The incubation was terminated by vacuumfiltration through the glass fiber plate bottom, followed with a 250 μlwash with assay buffer minus BSA and protease inhibitors. The platebottom was then sealed, scintillation fluid was added (Wallac Supermix,250 μl/well), and radioactivity was measured in a 96 well microtiterliquid scintillation counter.

[0203] IC₅₀ values are determined by polynomial regression and analzyedusing a MACRO program. An IC₅₀ value of less than about 5 μM ispreferred.

Example 10 Rat Pituitary Assay for Somatostatin Receptor Antagonists

[0204] This assay is designed to quantitate the activity of antagonistsof somatostatin that interact directly at the somatostatin receptor. Theassay facilitates discovery of agents which increase growth hormonesecretion by modulating the inhibitory effects of somatostatin. Asaforementioned, somatostatin (also abbreviated SRIF) inhibits GHsecretion in the anterior pituitary by binding to a high affinitymembrane-bound (and G-protein coupled) receptor which is couplednegatively to adenyl cyclase, thereby reducing intracellular levels ofcAMP that would otherwise facilitate, for example, secretion/release ofGH from cytoplasmic granules. Vasoactive intestinal peptide (VIP) is oneof several endogenous peptides that stimulates GH secretion by bindingto a high affinity membrane-bound receptor coupled to a Gprotein-dependent signal transduction pathway. VIP activates adenylatecyclase and produces increased intracellular cAMP levels. These peptidesmay be involved in the coordinate regulation of GH secretion underphysiologic conditions and be mediated through cAMP. The cell line usedin the screen is a clonal pituitary cell that synthesizes and secretesGH in response to VIP and SRIF, and many other regulatory hormones, asexpected for normal pituitary cells. The screen is designed toquantitate the ability of test agents to reverse SRIF's inhibition ofthe elevated intracellular cAMP levels produced by VIP.

[0205] In particular, cyclic AMP (cAMP) content of the pituitary cellline GH₄C₁ was used to differentiate somatostatin agonists fromantagonists. The method was similar to that described by L. J.Dorflinger et al. (“Somatostatin inhibits vasoactive intestinalpeptide-stimulated cyclic adenosine monophosphate accumulation in GHpituitary cells”, Endocrinology, 113, pp. 1541-50, 1983) with thefollowing modifications. Aliquots (50 μl) of GH₄C₁ cell suspension at1-2 million cells/ml were added to 50 μl of each solution of testcompound in Adenylyl Cyclase Activation FlashPlate® Assay plates fromNEN™ Life Science Products (catalog SMP004A). Putative somatostatinagonists or antagonists were typically tested at concentrations of 10, 1and 0.1 μM, in the presence of 100 nM vasoactive intestinal peptide(VIP; Sigma V3628) and 10 nM somatostatin 14 (cell culture tested, SigmaS1763). The FlashPlates®, which are coated with antibody against cAMPand contain scintillant integral to the plastic, are supplied as part ofa kit with all necessary reagents to estimate cAMP content of whole cellpreparations, including Stimulation Buffer, Detection Buffer, cAMPStandard, and [¹²⁵I]-cAMP Tracer. This afforded a convenient way toconduct a homogenous immunoradiometric assay of cAMP content in cellslysed in situ, following incubation of the cells with test compound.cAMP content in the GH₄C₁ cells was determined according to themanufacturer's instructions, by comparison with standards atconcentrations from 10 to 1,000 nM cAMP. In this assay, VIP increasedcAMP content of the GH₄C₁ cells, and somatostatin caused a partialinhibition. Test compounds acting as somatostatin antagonists weredetected by their tendancy to increase cAMP content in comparison tocontrol wells containing VIP and somatostatin but no test compound.Somatostatin agonists conversely decreased cAMP content.

[0206] IC₅₀ values are determined by polynomial regression and analzyedusing a MACRO program. An IC₅₀ value of less than about 5 μM ispreferred.

Example 11 Effect of a Somatostatin Antagonist on GH Release in 12 kgPigs

[0207] Studies indicate that concentrations of GH increase in small pigswithin 10 minutes of administration of somatostatin antagonists, andthen return to pre-treatment levels within 40 minutespost-administration.

[0208] The following protocol describes the effects of various doses ofa somatostatin antagonist on release of endogenous porcine GH (or pST,porcine somatatrophin). Methods used to evaluate effects of compounds onplasma GH concentrations in barrows (castrated male pigs) were similarto those reported by M. J. Estienne et al.,“Methyl-D,L-aspartate-induced growth hormone secretion in barrows:possible mechanisms of action”, Journal of Animal Science 74, pp.597-602, 1996, with the following modifications. Forty cross-bredbarrows weighing approximately 12 kg were acclimatized for 2 days at 10pigs per 36 sq. ft. pen, 4 pens per study, with feed (PS-9 swine starterdiet) and water provided ad libitum. To enhance uniformity, two pigs/penwere eliminated based on being smallest or largest, or for healthreasons, bringing the group size to 8 pigs/treatment. An equal number ofpigs in each pen received 1 of 4 possible treatments at random, i.e. oneof 3 doses of test compound or diluent alone. Compounds diluted inapproximately 1 ml/pig sterile saline were administered by intramuscularinjection into the rear leg (ham), about 1 minute after collection ofthe first blood sample into 7 ml heparinized evacuated tubes via jugularvenepuncture. Blood samples were similarly collected at 10 minuteintervals up to 40 minutes after injection of test compound or diluent.Plasma was separated by centrifugation and frozen at −20° C.).

Example 12 RIA Procedure for Determination of GH Levels in Plasma.

[0209] The present assay is used to determine GH levels (for example,porcine GH or canine GH) in plasma samples.

[0210] The double antibody radioimmunoassay (RIA) used to determineporcine GH concentrations in plasma samples was similar to thatdescribed by Y. N. Sinha et al., “Studies of GH secretion in mice by ahomologous radioimmunoassay for mouse GH”, Endocrinology, 91, pp.784-92,1972, and that of F. Cocola et al., “A rapid radioimmunoassay method ofgrowth hormone in dog plasma”, Proceedings of the Society forExperimental Biology and Medicine, 151, pp. 140-14, 1976. Modificationswere as follows. Native porcine GH (pGH) for radioiodination as tracer,canine GH for use as standard (cGH; AFP-1983B; the aminoacid sequence ofcanine and porcine GH are the same), and primary antibody (monkeyanti-cGH; AFP-21452) were supplied by A. F. Parlow, Harbor UCLA MedicalCenter. Recombinant porcine GH from Biogenesis was alternatively usedfor radioiodination as tracer. Radioiodinations were conducted byBiomedical Technologies Inc, Stoughton, Mass. Primary antibody (1:50,000or 1:100,000 final dilution), normal monkey serum (ICN 55988; 1:1,000final dilution), and plasma sample or standard (0.08 to 2.5 ng cGH/tube)were mixed and incubated for 2 hours at ambient temperature, then tracer(10,000 cpm/tube) was added and the incubation continued for a further20 hours at ambient temperature in a total volume of 500 μl. Secondaryantibody (goat anti-monkey IgG ICN 55418; final dilution 1:160) andpolyethyleneglycol 8,000 (final concentration 44 mg/ml) were added andmixed in a final volume of 1.6 ml. Tubes were incubated at 4° C. for 2hours with shaking, then they were centrifuged, supernates discarded,and the gamma-emission of the pellets determined.

[0211] Plasma growth hormone concentrations, expressed as ng/ml, werecalculated from the standard line following log-logit transformation.

1. A compound according to the formula A—G—Z—W or a pharmaceuticallyacceptable salt, solvates or hydrate thereof, wherein A is (C₆-C₁₀)aryl,(C₆-C₁₀)aryl-SO₂, (C₆-C₁₀)aryl-CH₂—, (C₆-C₁₀)arylcarbonyl,(C₁-C₉)heteroaryl, (C₁-C₉)heteroaryl-SO₂—, (C₁-C₉)heteroaryl-CH₂—; or(C₁-C₉)heteroarylcarbonyl; G is:

where B is (C₆-C₁₀)aryl or (C₁-C₉)heteroaryl, and X is CH₂, SO₂, orcarbonyl;

where X is CH₂, SO₂, or carbonyl; and R¹ and R^(1′) are eachindependently selected from H, CN, (C₁-C₈)alkyl-, and phenyl(CH₂)—,wherein said alkyl and phenyl groups are optionally substituted; or

wherein R² is H, (C₁-C₈)alkyl, or is selected from groups A above; and Eis selected from groups A above; W is (a):

wherein n is 2-5, R³ is selected from H, (C₁-C₈)alkyl-, andphenyl(CH₂)—, wherein said alkyl and phenyl groups are optionallysubstituted; R⁶ is selected from H, (C₁-C₈)alkyl-, and phenyl(CH₂)—,wherein said alkyl and phenyl groups are optionally substituted; R⁴ isselected from H, (C₁-C₈)alkyl-, and phenyl(CH₂)—, wherein said alkyl andphenyl groups are optionally substituted; or is

where groups R¹⁰, R¹¹ and R^(11′) are each, independently, selected fromH, (C₁-C₈)alkyl-, and phenyl(CH₂)—, wherein said alkyl and phenyl groupsare optionally substituted; R⁵ is H, (C₁-C₈)alkyl-, and phenyl(CH₂)—,wherein said alkyl and phenyl groups are optionally substituted, or is

wherein R¹² and R^(12′) are each independently selected from H,(C₁-C₈)alkyl-, and phenyl(CH₂)—, wherein said alkyl and phenyl groupsare optionally substituted; or W is (b)

wherein Q is selected from the group consisting of (C₆-C₁₀)aryl,(C₁-C₉)heteroaryl, (C₃-C₁₀)cycloalkyl, and (C₃-C₁₀)heterocycloalkyl; andR⁷, R⁸, and R⁹ are each independently selected from H, (C₁-C₈)alkyl-,and phenyl(CH₂)—, wherein said alkyl and phenyl groups are optionallysubstituted.
 2. The compound of claim 1 , wherein, independently, one ormore of groups A, B, E, and Q therein consist of, or comprise, a(C₆-C₁₀)aryl group, selected from phenyl and naphthyl.
 3. The compoundof claim 1 , wherein, independently, one or more of groups A, B, E, andQ therein consist of, or comprise, a (C₁-C₉)heteroaryl group, selectedfrom furyl, thienyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl,isoxazolyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl,1,3,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-oxadiazolyl,1,3,5-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, pyridyl,pyrimidyl, pyrazinyl, pyridazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl,1,3,5-triazinyl, pyrazolo[3,4-b]pyridinyl, cinnolinyl, pteridinyl,purinyl, 6,7-dihydro-5H-[1]pyrindinyl, benzo[b]thiophenyl, 5, 6, 7,8-tetrahydro-quinolin-3-yl, benzoxazolyl, benzothiazolyl,benzisothiazolyl, benzisoxazolyl, benzimidazolyl, thianaphthenyl,isothianaphthenyl, benzofuranyl, isobenzofuranyl, isoindolyl, indolyl,indolizinyl, indazolyl, isoquinolyl, quinolyl, phthalazinyl,quinoxalinyl, quinazolinyl, and benzoxazinyl.
 4. The compound of claim 1, wherein group Q therein is selected from (a) a (C₆-C₁₀)aryl group,selected from phenyl and naphthyl; (b) a (C₁-C₉)heteroaryl group,selected from furyl, thienyl, thiazolyl, pyrazolyl, isothiazolyl,oxazolyl, isoxazolyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl,1,3,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-oxadiazolyl,1,3,5-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, pyridyl,pyrimidyl, pyrazinyl, pyridazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl,1,3,5-triazinyl, pyrazolo[3,4-b]pyridinyl, cinnolinyl, pteridinyl,purinyl, 6,7-dihydro-5H-[1]pyrindinyl, benzo[b]thiophenyl, 5, 6, 7,8-tetrahydro-quinolin-3-yl, benzoxazolyl, benzothiazolyl,benzisothiazolyl, benzisoxazolyl, benzimidazolyl, thianaphthenyl,isothianaphthenyl, benzofuranyl, isobenzofuranyl, isoindolyl, indolyl,indolizinyl, indazolyl, isoquinolyl, quinolyl, phthalazinyl,quinoxalinyl, quinazolinyl, and benzoxazinyl; (c) a (C₃-C₁₀)cycloalkylgroup, selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl,cycloheptenyl, 1,3-cyclobutadienyl, 1,3-cyclopentadienyl,1,3-cyclohexadienyl, 1,4-cyclohexadienyl, 1,3-cycloheptadienyl,1,4-cycloheptadienyl, 1,3,5-cycloheptatrienyl, bicyclo[3.2.1]octane,bicyclo [2.2.1] heptane and the norborn-2-ene unsaturated form thereof;and (d) a (C₃-C₁₀)heterocycloalkyl group, selected from pyrrolidinyl,tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, pyranyl,thiopyranyl, aziridinyl, oxiranyl, methylenedioxyl, chromenyl,isoxazolidinyl, 1,3-oxazolidin-3-yl, isothiazolidinyl,1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl, 1,3-pyrazolidin-1-yl,piperidinyl, thiomorpholinyl, 1,2-tetrahydrothiazin-2-yl,1,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazinyl, morpholinyl,1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl,tetrahydroazepinyl, piperazinyl, and chromanyl.
 5. A compound accordingto claim 1 selected from the group consisting of:6-Amino-2-[2-[(biphenyl-4-ylmethyl)-amino]-3-(1H-indol-3-yl)-propionylamino]-hexanoicacid methyl ester;2-{3-(3-Fluoro-phenyl)-2-[2-(toluene-4-sulfonylamino)-acetylamino]-propionylamino}-5-guanidino-pentanoicacid methyl ester;6-Amino-2-[2-[(biphenyl-4-carbonyl)-amino]-3-(1H-indol-3-yl)-propionylamino]-hexanoicacid methyl ester;2-{2-[(Biphenyl-4-carbonyl)-amino]-3,3-diphenyl-propionylamino}-5-guanidino-pentanoicacid methyl ester;6-Amino-2-[2-[(biphenyl-4-carbonyl)-amino]-3-(1H-indol-3-yl)-propionylamino]-hexanoicacid tert-butyl ester;6-Amino-2-[2-(2-benzenesulfonylamino-2-methyl-propionylamino)-3-(1H-indol-3-yl)-propionylamino]-hexanoicacid tert-butyl ester; and
 6. A compound according to claim 5 selectedfrom the group consisting of:6-Amino-2-[2-[(biphenyl-4-carbonyl)-amino]-3-(1H-indol-3-yl)-propionylamino]-hexanoicacid tert-butyl ester; and6-Amino-2-[2-(2-benzenesulfonylamino-2-methyl-propionylamino)-3-(1H-indol-3-yl)-propionylamino]-hexanoicacid tert-butyl ester.
 7. A compound according to claim 1 , wherein theZ group thereof has the stereospecificity


8. A compound according to claim 7 , wherein the Z group defines anL-amino acid selected from the group consisting of L-tryptophanyl,L-histidinyl, L-3-methylhistidinyl,L-phenylalaninyl-L-diphenylalaninyl-, L-2-fluorophenylalaninyl-,L-3-fluorophenylalaninyl-, L-4-fluorophenylalaninyl-, and L-tyrosinyl-.9. A compound according to claim 8 wherein said Z group thereof isL-tryptophanyl-.
 10. A compound according to claim 1 , wherein the Zgroup thereof has the stereospecificity


11. A compound according to claim 10 , wherein the Z group defines anD-amino acid that is D-tryptophanyl.
 12. A compound according to claim11 wherein said Z group thereof is D-tryptophanyl-.
 13. A compoundaccording to claim 1 , wherein the W group thereof has an absolutestereospecific configuration at the indicated position which correspondsto the that of the α-carbon of L-amino acids.


14. A compound according to claim 13 , wherein the W group is anL-lysine group or a (C₁-C₈)alkyl ester thereof, an L-ornithine group ora (C₁-C₈)alkyl ester thereof, an L-arginine group or a (C₁-C₈)alkylester thereof, an L-histidine group, or a (C₁-C₈)alkyl ester thereof, oran L-3-methylhistidine group, or a (C₁-C₈)alkyl ester thereof.
 15. Acompound according to claim 14 , wherein said W group is a (C₁-C₈)alkylester of L-lysine.
 16. A compound according to claim 1 wherein R¹ is(C₁-C₈)alkyl- or phenyl(CH₂)— and said alkyl or phenyl group isoptionally substituted by one or more halo or trifluoro(C₁-C₈)alkylgroups.
 17. A compound according to claim 1 wherein R¹ is (C₁-C₈)alkyl-or phenyl(CH₂)— and said alkyl or phenyl group is optionally substitutedby one or more halo or trifluoro(C₁-C₈)alkyl groups.
 18. A compoundaccording to claim 1 wherein R² is (C₁-C₃)alkyl-, optionally substitutedby one or more halo or trifluoro(C₁-C₈)alkyl groups.
 19. A compoundaccording to claim 1 wherein R² is (C₁-C₈)alkyl-, optionally substitutedby one or more halo or trifluoro(C₁-C₈)alkyl groups.
 20. A compoundaccording to claim 1 wherein one or more of R³, R⁴, R⁵, and R⁶ is(C₁-C₈)alkyl- or phenyl(CH₂)—, and said alkyl or phenyl group isoptionally substituted by one or more halo or trifluoro(C₁-C₈)alkylgroups.
 21. A compound according to claim 1 wherein one or more of R⁷,R⁸, and R⁹ is (C₁-C₈)alkyl- or phenyl(CH₂)—, and said alkyl or phenylgroup is optionally substituted by one or more halo ortrifluoro(C₁-C₈)alkyl groups.
 22. A compound according to claim 1wherein one or more of R¹⁰, R¹¹, and R^(11′) is (C₁-C₈)alkyl- orphenyl(CH₂)—, and said alkyl or phenyl group is optionally substitutedby one or more halo or trifluoro(C₁-C₈)alkyl groups.
 23. A compoundaccording to claim 1 wherein one or more of R¹² and R^(12′) is(C₁-C₈)alkyl- or phenyl(CH₂)—, and said alkyl or phenyl group isoptionally substituted by one or more halo or trifluoro(C₁-C₈)alkylgroups.
 24. A compound according to claim 1 wherein atrifluoro(C₁-C₈)alkyl substituent present on a B, E, R¹, R^(1′), R², R³,R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R^(11′), R¹² or R^(12′) group thereofis trifluoromethyl.
 25. A pharmaceutical composition for increasinggrowth hormone secretion in a mammal, comprising an effective amount ofa compound according to claim 1 , and a pharmaceutical carrier.
 26. Apharmaceutical composition for increasing secretion of gastrin orglucagon in a mammal, comprising an effective amount of a compoundaccording to claim 1 , and a pharmaceutical carrier.
 27. Apharmaceutical composition for inhibiting the binding of somatostatin tothe sst2 receptor therefor, comprising an effective amount of a compoundaccording to claim 1 , and a pharmaceutical carrier.
 28. A method forincreasing growth hormone secretion in a mammal, comprisingadministering an effective amount of a pharmaceutical compositionaccording to claim 25 .
 29. A method for increasing secretion of gastrinor glucagon in a mammal, comprising administering an effective amount ofa pharmaceutical composition according to claim 25 .
 30. A method fordecreasing somatostatin-induced downregulation of growth hormonesecretion in a mammal, comprising administering an effective amount of apharmaceutical composition according to claim 25 .
 31. A pharmaceuticalcomposition useful to cause sustained release of growth hormone in amammal in need thereof, comprising a compound according to claim 1 , anda pharmaceutical carrier.
 32. A method for facilitating the sustainedsecretion of growth hormone in a mammal in need thereof, wherein saidmammal possesses: (a) a defect in the expression of the encodingnucleotide sequence for growth hormone, the processing of resultantmRNA, or the translation or intracellular processing and packaging of GHor precursor polypeptide thereof; or (b) an allele of the growth hormonegene which codes for a growth hormone polypeptide that is insufficientlyactive; which comprises administering an effective amount of apharmaceutical composition according to claim 25 .
 33. A method fortreating a human for one or more symptoms of insufficient growth hormonesecretion, wherein said symptom is selected from frailty, hypoglycemia,wrinkled skin, slow skeletal growth, reduced immune function, andreduced organ function, comprising administering an effective amount ofa pharmaceutical composition according to claim 25 .
 34. A method fortreating a non-human mammal to enhance the growth and performancethereof, comprising administering an effective amount of apharmaceutical composition according to claim 25 .
 35. A pharmaceuticalcomposition according to claim 25 further comprising growth hormonereleasing peptide (GHRP) or growth hormone releasing hormone (GHRH). 36.A method for increasing growth hormone secretion in a mammal, comprisingadministering an effective amount of a pharmaceutical compositionaccording to claim 35 .
 37. A method for increasing growth hormonesecretion in a mammal, comprising administering an effective amount of apharmaceutical composition according to claim 25 , and a furthercomposition comprising growth hormone releasing peptide (GHRP) or growthhormone releasing hormone (GHRH).
 38. A compound according to claim 13 ,wherein the W group comprises an L-diaminopimelic, L-canavanine,L-2,4-diaminobutyric, L-5-hydroxylysine, or L-epsilon-N-methyllysinegroup, or a (C₁-C₈)alkyl ester of any thereof.